Andrew Spakowitz
Tang Family Foundation Chair of the Department of Chemical Engineering, Professor of Chemical Engineering, of Materials Science and Engineering and, by courtesy, of Applied Physics
Bio
Theory and Computation of Biological Processes and Complex Materials
The Spakowitz lab is engaged in projects that address fundamental chemical and physical phenomena underlying a range of biological processes and soft-material applications. Current research in our lab focuses on four main research themes: chromosomal organization and dynamics, protein self-assembly, polymer membranes, and charge transport in conducting polymers. These broad research areas offer complementary perspectives on chemical and physical processes, and we leverage this complementarity throughout our research. Our approach draws from a diverse range of theoretical and computational methods, including analytical theory of semiflexible polymers, polymer field theory, continuum elastic mechanics, Brownian dynamics simulation, equilibrium and dynamic Monte Carlo simulations, and analytical theory and numerical simulations of reaction-diffusion phenomena. A common thread in our work is the need to capture phenomena over many length and time scales, and our flexibility in research methodologies provides us with the critical tools to address these complex multidisciplinary problems.
Academic Appointments
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Professor, Chemical Engineering
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Professor, Materials Science and Engineering
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Professor (By courtesy), Applied Physics
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Member, Bio-X
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Affiliate, Precourt Institute for Energy
Administrative Appointments
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Chair of the Department of Chemical Engineering, Stanford University (2022 - Present)
Honors & Awards
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Terman Fellow, Stanford University (2006-2009)
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CAREER Award, NSF (2009)
Professional Education
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PhD, California Institute of Technology (2004)
Current Research and Scholarly Interests
Theory and computation of biological processes and complex materials
2024-25 Courses
- Applied Mathematics in Chemical Engineering
CHEMENG 105 (Spr) -
Independent Studies (14)
- Advanced Undergraduate Research
CHEM 190 (Aut, Win, Spr, Sum) - Directed Instruction/Reading
CHEM 90 (Aut, Win, Spr, Sum) - Directed Reading in Biophysics
BIOPHYS 399 (Aut, Win, Spr, Sum) - Directed Studies in Applied Physics
APPPHYS 290 (Aut, Win, Spr, Sum) - Graduate Research
BIOPHYS 300 (Aut, Win, Spr, Sum) - Graduate Research in Chemical Engineering
CHEMENG 600 (Aut, Win, Spr, Sum) - Master's Research
MATSCI 200 (Aut, Win, Spr, Sum) - Ph.D. Research
MATSCI 300 (Aut, Win, Spr, Sum) - Practical Training
MATSCI 299 (Aut, Win, Spr, Sum) - Research
PHYSICS 490 (Aut, Win, Spr, Sum) - Research and Special Advanced Work
CHEM 200 (Aut, Win, Spr, Sum) - Research in Chemistry
CHEM 301 (Aut, Win, Spr, Sum) - Undergraduate Honors Research in Chemical Engineering
CHEMENG 190H (Aut, Win, Spr, Sum) - Undergraduate Research in Chemical Engineering
CHEMENG 190 (Aut, Win, Spr, Sum)
- Advanced Undergraduate Research
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Prior Year Courses
2022-23 Courses
- Special Topics in Biopolymer Physics
CHEMENG 514 (Aut) - Undergraduate Practical Training
CHEMENG 199 (Sum)
2021-22 Courses
- Applied Mathematics in the Chemical and Biological Sciences
CHEMENG 300, CME 330 (Aut) - Data Science and Machine Learning Approaches in Chemical and Materials Engineering
CHEMENG 177, CHEMENG 277, MATSCI 166, MATSCI 176 (Spr) - Special Topics in Biopolymer Physics
CHEMENG 514 (Aut, Win, Spr, Sum) - Undergraduate Practical Training
CHEMENG 199 (Sum)
- Special Topics in Biopolymer Physics
Stanford Advisees
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Doctoral Dissertation Reader (AC)
Jacob Horne, Dean Lahana, Srikant Sagireddy, Tee Udomlumleart -
Postdoctoral Faculty Sponsor
Daeyeon Kim -
Doctoral Dissertation Advisor (AC)
Thomas Habte, Angelika Hirsch, Zachary Montgomerie -
Doctoral Dissertation Co-Advisor (AC)
Gabi Basel, Goldie Roth, Lucy Wang, William Xu
All Publications
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The lysogenic filamentous Pseudomonas bacteriophage phage Pf slows mucociliary transport.
PNAS nexus
2024; 3 (9): pgae390
Abstract
Pseudomonas aeruginosa is a major pulmonary pathogen causing chronic pulmonary infections in people with cystic fibrosis (CF). The P. aeruginosa filamentous and lysogenic bacteriophage, Pf phage, is abundant in the airways of many people with CF and has been associated with poor outcomes in a cross-sectional cohort study. Previous studies have identified roles for Pf phage in biofilm formation, specifically forming higher-order birefringent, liquid crystals when in contact with other biopolymers in biofilms. Liquid crystalline biofilms are more adherent and viscous than those without liquid crystals. A key feature of biofilms is to enhance bacterial adherence and resist physical clearance. The effect of Pf phage on mucociliary transport is unknown. We found that primary CF and non-CF nasal epithelial cells cultured at air-liquid interface treated with Pf phage exhibit liquid crystalline structures in the overlying mucus. On these cell cultures, Pf phage entangles cilia but does not affect ciliary beat frequency. In both these in vitro cell cultures and in an ex vivo porcine trachea model, introduction of Pf phage decreases mucociliary transport velocity. Pf phage also blocks the rescue of mucociliary transport by CF transmembrane conductance regulator modulators in CF cultures. Thus, Pf phage may contribute to the pathogenesis of P. aeruginosa-associated CF lung disease via induction of liquid crystalline characteristics to airway secretions, leading to impaired mucociliary transport. Targeting Pf phage may be useful in treatment CF as well as other settings of chronic P. aeruginosa infections.
View details for DOI 10.1093/pnasnexus/pgae390
View details for PubMedID 39301510
View details for PubMedCentralID PMC11412248
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Determining mesoscale chromatin structure parameters from spatially correlated cleavage data using a coarse-grained oligonucleosome model.
bioRxiv : the preprint server for biology
2024
Abstract
The three-dimensional structure of chromatin has emerged as an important feature of eukaryotic gene regulation. Recent technological advances in DNA sequencing-based assays have revealed locus- and chromatin state-specific structural patterns at the length scale of a few nucleosomes (~1 kb). However, interpreting these data sets remains challenging. Radiation-induced correlated cleavage of chromatin (RICC-seq) is one such chromatin structure assay that maps DNA-DNA-contacts at base pair resolution by sequencing single-stranded DNA fragments released from irradiated cells. Here, we develop a flexible modeling and simulation framework to enable the interpretation of RICC-seq data in terms of oligonucleosome structure ensembles. Nucleosomes are modeled as rigid bodies with excluded volume and adjustable DNA wrapping, connected by linker DNA modeled as a worm-like chain. We validate the model's parameters against cryo-electron microscopy and sedimentation data. Our results show that RICC-seq is sensitive to nucleosome spacing, nucleosomal DNA wrapping, and the strength of inter-nucleosome interactions. We show that nucleosome repeat lengths consistent with orthogonal assays can be extracted from experimental RICC-seq data using a 1D convolutional neural net trained on RICC-seq signal predicted from simulated ensembles. We thus provide a suite of analysis tools that add quantitative structural interpretability to RICC-seq experiments.
View details for DOI 10.1101/2024.07.28.605011
View details for PubMedID 39131347
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Physical modeling of nucleosome clustering in euchromatin resulting from interactions between epigenetic reader proteins.
Proceedings of the National Academy of Sciences of the United States of America
2024; 121 (26): e2317911121
Abstract
Euchromatin is an accessible phase of genetic material containing genes that encode proteins with increased expression levels. The structure of euchromatin in vitro has been described as a 30-nm fiber formed from ordered nucleosome arrays. However, recent advances in microscopy have revealed an in vivo euchromatin architecture that is much more disordered, characterized by variable-length linker DNA and sporadic nucleosome clusters. In this work, we develop a theoretical model to elucidate factors contributing to the disordered in vivo architecture of euchromatin. We begin by developing a 1D model of nucleosome positioning that captures the interactions between bound epigenetic reader proteins to predict the distribution of DNA linker lengths between adjacent nucleosomes. We then use the predicted linker lengths to construct 3D chromatin configurations consistent with the physical properties of DNA within the nucleosome array, and we evaluate the distribution of nucleosome cluster sizes in those configurations. Our model reproduces experimental cluster-size distributions, which are dramatically influenced by the local pattern of epigenetic marks and the concentration of reader proteins. Based on our model, we attribute the disordered arrangement of euchromatin to the heterogeneous binding of reader proteins and subsequent short-range interactions between bound reader proteins on adjacent nucleosomes. By replicating experimental results with our physics-based model, we propose a mechanism for euchromatin organization in the nucleus that impacts gene regulation and the maintenance of epigenetic marks.
View details for DOI 10.1073/pnas.2317911121
View details for PubMedID 38900792
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Local changes in protein filament properties drive large-scale membrane transformations involved in endosome tethering and fusion.
Soft matter
2024
Abstract
Large-scale cellular transformations are triggered by subtle physical and structural changes to individual biomacromolecular and membrane components. A prototypical example of such an event is the orchestrated fusion of membranes within an endosome that enables transport of cargo and processing of biochemical moieties. In this work, we demonstrate how protein filaments on the endosomal membrane surface can leverage a rigid-to-flexible transformation to elicit a large-scale change in membrane flexibility to enable membrane fusion. We develop a polymer field-theoretic model that captures molecular alignment arising from nematic interactions with varying surface density and fraction of flexible filaments, which are biologically controlled within the endosomal membrane. We then predict the collective elasticity of the filament brush in response to changes in the filament alignment, predicting a greater than 20-fold increase of the effective membrane elasticity over the bare membrane elasticity that is triggered by filament alignment. These results show that the endosome can modulate the filament properties to orchestrate membrane fluidization that facilitates vesicle fusion, providing an example of how active processes that modulate local molecular properties can result in large-scale transformations that are essential to cellular survival.
View details for DOI 10.1039/d4sm00299g
View details for PubMedID 38881306
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Air-liquid intestinal cell culture allows in situ rheological characterization of intestinal mucus.
APL bioengineering
2024; 8 (2): 026112
Abstract
Intestinal health heavily depends on establishing a mucus layer within the gut with physical properties that strike a balance between being sufficiently elastic to keep out harmful pathogens yet viscous enough to flow and turnover the contents being digested. Studies investigating dysfunction of the mucus layer in the intestines are largely confined to animal models, which require invasive procedures to collect the mucus fluid. In this work, we develop a nondestructive method to study intestinal mucus. We use an air-liquid interface culture of primary human intestinal epithelial cells that exposes their apical surface to allow in situ analysis of the mucus layer. Mucus collection is not only invasive but also disrupts the mucus microstructure, which plays a crucial role in the interaction between mucus and the gut microbiome. Therefore, we leverage a noninvasive rheology technique that probes the mechanical properties of the mucus without removal from the culture. Finally, to demonstrate biomedical uses for this cell culture system, we characterize the biochemical and biophysical properties of intestinal mucus due to addition of the cytokine IL-13 to recapitulate the gut environment of Nippostrongylus brasiliensis infection.
View details for DOI 10.1063/5.0187974
View details for PubMedID 38721267
View details for PubMedCentralID PMC11078553
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Pf bacteriophages hinder sputum antibiotic diffusion via electrostatic binding.
Science advances
2024; 10 (22): eadl5576
Abstract
Despite great progress in the field, chronic Pseudomonas aeruginosa (Pa) infections remain a major cause of mortality in patients with cystic fibrosis (pwCF), necessitating treatment with antibiotics. Pf is a filamentous bacteriophage produced by Pa and acts as a structural element in Pa biofilms. Pf presence has been associated with antibiotic resistance and poor outcomes in pwCF, although the underlying mechanisms are unclear. We have investigated how Pf and sputum biopolymers impede antibiotic diffusion using pwCF sputum and fluorescent recovery after photobleaching. We demonstrate that tobramycin interacts with Pf and sputum polymers through electrostatic interactions. We also developed a set of mathematical models to analyze the complex observations. Our analysis suggests that Pf in sputum reduces the diffusion of charged antibiotics due to a greater binding constant associated with organized liquid crystalline structures formed between Pf and sputum polymers. This study provides insights into antibiotic tolerance mechanisms in chronic Pa infections and may offer potential strategies for novel therapeutic approaches.
View details for DOI 10.1126/sciadv.adl5576
View details for PubMedID 38820163
View details for PubMedCentralID PMC11141622
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Exploration of Phase Behavior in Asymmetric Semiflexible Polyelectrolyte Mixtures Using Polymer Field Theory
MACROMOLECULES
2024; 57 (5): 2505-2519
View details for DOI 10.1021/acs.macromol.3c02197
View details for Web of Science ID 001179572600001
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Preferred states of single DNA molecules in crowded solutions
CELL PRESS. 2024: 460A
View details for Web of Science ID 001194120702630
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Effect of local active fluctuations on structure and dynamics of flexible biopolymers.
Soft matter
2024
Abstract
Active fluctuations play a significant role in the structure and dynamics of biopolymers (e.g. chromatin and cytoskeletal proteins) that are instrumental in the functioning of living cells. For a large range of experimentally accessible length and time scales, these polymers can be represented as flexible chains that are subjected to spatially and temporally varying fluctuating forces. In this work, we introduce a mathematical framework that correlates the spatial and temporal patterns of the fluctuations to different observables that describe the dynamics and conformations of the polymer. We demonstrate the power of this approach by analyzing the case of a point fluctuation on the polymer with an exponential decay of correlation in time with a finite time constant. Specifically, we identify the length and time scale over which the behavior of the polymer exhibits a significant departure from the behavior of a Rouse chain and the range of impact of the fluctuation along the chain. Furthermore, we show that the conformation of the polymer retains the memory of the active fluctuation from earlier times. Altogether, this work sets the basis for understanding and interpreting the role of spatio-temporal patterns of fluctuations in the dynamics, conformation, and functionality of biopolymers in living cells.
View details for DOI 10.1039/d3sm01491f
View details for PubMedID 38226903
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Conformational Statistics of Ribbon-like Chains
MACROMOLECULES
2023; 56 (20): 8359-8368
View details for DOI 10.1021/acs.macromol.3c01430
View details for Web of Science ID 001091129100001
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Leveraging polymer modeling to reconstruct chromatin connectivity from live images.
Biophysical journal
2023
Abstract
Chromosomal dynamics plays a central role in a number of critical biological processes, such as transcriptional regulation, genetic recombination, and DNA replication. However, visualization of chromatin is generally limited to live imaging of a few fluorescently labeled chromosomal loci or high-resolution reconstruction of multiple loci from a single time frame. To aid in mapping the underlying chromosomal structure based on parsimonious experimental measurements, we present an exact analytical expression for the evolution of the polymer configuration based on a flexible-polymer model, and we propose an algorithm that tracks the polymer configuration from live images of chromatin marked with several fluorescent marks. Our theory identifies the resolution of microscopy needed to achieve high-accuracy tracking for a given spacing of markers, establishing the statistical confidence in the assignment of genome identity to the visualized marks. We then leverage experimental data of locus-tracking measurements to demonstrate the validity of our modeling approach and to establish a basis for the design of experiments with a desired resolution. Altogether, this work provides a computational approach founded on polymer physics that vastly improves the interpretation of in vivo measurements of biopolymer dynamics.
View details for DOI 10.1016/j.bpj.2023.08.001
View details for PubMedID 37542372
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Interplay of Polymer Structure, Solvent Ordering, and Charge Fluctuations in Polyelectrolyte Solution Thermodynamics
MACROMOLECULES
2022
View details for DOI 10.1021/acs.macromol.2c01826
View details for Web of Science ID 000906122800001
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Closing the loop between microstructure and charge transport in conjugated polymers by combining microscopy and simulation.
Proceedings of the National Academy of Sciences of the United States of America
2022; 119 (46): e2204346119
Abstract
A grand challenge in materials science is to identify the impact of molecular composition and structure across a range of length scales on macroscopic properties. We demonstrate a unified experimental-theoretical framework that coordinates experimental measurements of mesoscale structure with molecular-level physical modeling to bridge multiple scales of physical behavior. Here we apply this framework to understand charge transport in a semiconducting polymer. Spatially-resolved nanodiffraction in a transmission electron microscope is combined with a self-consistent framework of the polymer chain statistics to yield a detailed picture of the polymer microstructure ranging from the molecular to device relevant scale. Using these data as inputs for charge transport calculations, the combined multiscale approach highlights the underrepresented role of defects in existing transport models. Short-range transport is shown to be more chaotic than is often pictured, with the drift velocity accounting for a small portion of overall charge motion. Local transport is sensitive to the alignment and geometry of polymer chains. At longer length scales, large domains and gradual grain boundaries funnel charges preferentially to certain regions, creating inhomogeneous charge distributions. While alignment generally improves mobility, these funneling effects negatively impact mobility. The microstructure is modified in silico to explore possible design rules, showing chain stiffness and alignment to be beneficial while local homogeneity has no positive effect. This combined approach creates a flexible and extensible pipeline for analyzing multiscale functional properties and a general strategy for extending the accesible length scales of experimental and theoretical probes by harnessing their combined strengths.
View details for DOI 10.1073/pnas.2204346119
View details for PubMedID 36343237
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Semiflexible polymer solutions. II. Fluctuations and Frank elastic constants.
The Journal of chemical physics
2022; 157 (15): 154906
Abstract
We study the collective elastic behavior of semiflexible polymer solutions in a nematic liquid-crystalline state using polymer field theory. Our polymer field-theoretic model of semiflexible polymer solutions is extended to include second-order fluctuation corrections to the free energy, permitting the evaluation of the Frank elastic constants based on orientational order fluctuations in the nematic state. Our exact treatment of wormlike chain statistics permits the evaluation of behavior from the nematic state, thus accurately capturing the impact of single-chain behavior on collective elastic response. Results for the Frank elastic constants are presented as a function of aligning field strength and chain length, and we explore the impact of conformation fluctuations and hairpin defects on the twist, splay, and bend moduli. Our results indicate that the twist elastic constant Ktwist is smaller than both bend and splay constants (Kbend and Ksplay, respectively) for the entire range of polymer rigidity. Splay and bend elastic constants exhibit regimes of dominance over the range of chain stiffness, where Ksplay > Kbend for flexible polymers (large-N limit) while the opposite is true for rigid polymers. Theoretical analysis also suggests the splay modulus tracks exactly to that of the end-to-end distance in the transverse direction for semiflexible polymers at intermediate to large-N. These results provide insight into the role of conformation fluctuations and hairpin defects on the collective response of polymer solutions.
View details for DOI 10.1063/5.0120526
View details for PubMedID 36272793
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Rheological Characterization and Theoretical Modeling Establish Molecular Design Rules for Tailored Dynamically Associating Polymers.
ACS central science
2022; 8 (9): 1318-1327
Abstract
Dynamically associating polymers have long been of interest due to their highly tunable viscoelastic behavior. Many applications leverage this tunability to create materials that have specific rheological properties, but designing such materials is an arduous, iterative process. Current models for dynamically associating polymers are phenomenological, assuming a structure for the relationship between association kinetics and network relaxation. We present the Brachiation model, a molecular-level theory of a polymer network with dynamic associations that is rooted in experimentally controllable design parameters, replacing the iterative experimental process with a predictive model for how experimental modifications to the polymer will impact rheological behavior. We synthesize hyaluronic acid chains modified with supramolecular host-guest motifs to serve as a prototypical dynamic network exhibiting tunable physical properties through control of polymer concentration and association rates. We use dynamic light scattering microrheology to measure the linear viscoelasticity of these polymers across six decades in frequency and fit our theory parameters to the measured data. The parameters are then altered by a magnitude corresponding to changes made to the experimental parameters and used to obtain new rheological predictions that match the experimental results well, demonstrating the ability for this theory to inform the design process of dynamically associating polymeric materials.
View details for DOI 10.1021/acscentsci.2c00432
View details for PubMedID 36188349
View details for PubMedCentralID PMC9523779
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Rheological Characterization and Theoretical Modeling Establish Molecular Design Rules for Tailored Dynamically Associating Polymers
ACS CENTRAL SCIENCE
2022
View details for DOI 10.1021/acscentsci.2c00432
View details for Web of Science ID 000858451600001
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Active and thermal fluctuations in multi-scale polymer structure and dynamics.
Soft matter
2022
Abstract
The presence of athermal noise or biological fluctuations control and maintain crucial life-processes. In this work, we present an exact analytical treatment of the dynamic behavior of a flexible polymer chain that is subjected to both thermal and active forces. Our model for active forces incorporates temporal correlation associated with the characteristic time scale and processivity of enzymatic function (driven by ATP hydrolysis), leading to an active-force time scale that competes with relaxation processes within the polymer chain. We analyze the structure and dynamics of an active-Brownian polymer using our exact results for the dynamic structure factor and the looping time for the chain ends. The spectrum of relaxation times within a polymer chain implies two different behaviors at small and large length scales. Small length-scale relaxation is faster than the active-force time scale, and the dynamic and structural behavior at these scales are oblivious to active forces and, are thus governed by the true thermal temperature. Large length-scale behavior is governed by relaxation times that are much longer than the active-force time scale, resulting in an effective active-Brownian temperature that dramatically alters structural and dynamic behavior. These complex multi-scale effects imply a time-dependent temperature that governs living and non-equilibrium systems, serving as a unifying concept for interpreting and predicting their physical behavior.
View details for DOI 10.1039/d2sm00593j
View details for PubMedID 36000419
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Biochemical, biophysical, and immunological characterization of respiratory secretions in severe SARS-CoV-2 infections.
JCI insight
2022; 7 (12)
Abstract
Thick, viscous respiratory secretions are a major pathogenic feature of COVID-19, but the composition and physical properties of these secretions are poorly understood. We characterized the composition and rheological properties (i.e., resistance to flow) of respiratory secretions collected from intubated COVID-19 patients. We found the percentages of solids and protein content were greatly elevated in COVID-19 compared with heathy control samples and closely resembled levels seen in cystic fibrosis, a genetic disease known for thick, tenacious respiratory secretions. DNA and hyaluronan (HA) were major components of respiratory secretions in COVID-19 and were likewise abundant in cadaveric lung tissues from these patients. COVID-19 secretions exhibited heterogeneous rheological behaviors, with thicker samples showing increased sensitivity to DNase and hyaluronidase treatment. In histologic sections from these same patients, we observed increased accumulation of HA and the hyaladherin versican but reduced tumor necrosis factor-stimulated gene-6 staining, consistent with the inflammatory nature of these secretions. Finally, we observed diminished type I interferon and enhanced inflammatory cytokines in these secretions. Overall, our studies indicated that increases in HA and DNA in COVID-19 respiratory secretion samples correlated with enhanced inflammatory burden and suggested that DNA and HA may be viable therapeutic targets in COVID-19 infection.
View details for DOI 10.1172/jci.insight.152629
View details for PubMedID 35730564
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Coarse-Grained Modeling Reveals the Impact of Supercoiling and Loop Length in DNA Looping Kinetics.
Biophysical journal
2022
Abstract
Measurements of protein-mediated DNA looping reveal that in vivo conditions favor the formation of loops shorter than those that occur in vitro, yet the precise physical mechanisms underlying this shift remain unclear. To understand the extent to which in vivo supercoiling may explain these shifts, we develop a theoretical model based on coarse-grained molecular simulation and analytical transition-state theory, enabling us to map out looping energetics and kinetics as a function of two key biophysical parameters-superhelical density and loop length. We show that loops on the scale of a persistence length respond to supercoiling over a much wider range of superhelical densities and to a larger extent than longer loops. This effect arises from a tendency for loops to be centered on the plectonemic end region, which bends progressively more tightly with superhelical density. This trend reveals a mechanism by which supercoiling favors shorter loop lengths. In addition, our model predicts a complex kinetic response to supercoiling for a given loop length, governed by a competition between an enhanced rate of looping due to torsional buckling and a reduction in looping rate due to chain straightening as the plectoneme tightens at higher superhelical densities. Together, these effects lead to a flattening of the kinetic response to supercoiling within the physiological range for all but the shortest loops. Using experimental estimates for in vivo superhelical densities, we discuss our model's ability to explain available looping data, highlighting both the importance of supercoiling as a regulatory force in genetics and the additional complexities of looping phenomena in vivo.
View details for DOI 10.1016/j.bpj.2022.04.009
View details for PubMedID 35421389
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Biochemical, Biophysical, and Immunological Characterization of Respiratory Secretions in Severe SARS-CoV-2 (COVID-19) Infections.
medRxiv : the preprint server for health sciences
2022
Abstract
Thick, viscous respiratory secretions are a major pathogenic feature of COVID-19 disease, but the composition and physical properties of these secretions are poorly understood. We characterized the composition and rheological properties (i.e. resistance to flow) of respiratory secretions collected from intubated COVID-19 patients. We find the percent solids and protein content are greatly elevated in COVID-19 compared to heathy control samples and closely resemble levels seen in cystic fibrosis, a genetic disease known for thick, tenacious respiratory secretions. DNA and hyaluronan (HA) are major components of respiratory secretions in COVID-19 and are likewise abundant in cadaveric lung tissues from these patients. COVID-19 secretions exhibit heterogeneous rheological behaviors with thicker samples showing increased sensitivity to DNase and hyaluronidase treatment. In histologic sections from these same patients, we observe increased accumulation of HA and the hyaladherin versican but reduced tumor necrosis factora"stimulated gene-6 (TSG6) staining, consistent with the inflammatory nature of these secretions. Finally, we observed diminished type I interferon and enhanced inflammatory cytokines in these secretions. Overall, our studies indicate that increases in HA and DNA in COVID-19 respiratory secretion samples correlate with enhanced inflammatory burden and suggest that DNA and HA may be viable therapeutic targets in COVID-19 infection.
View details for DOI 10.1101/2022.03.28.22272848
View details for PubMedID 35411348
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Diffusion and distal linkages govern interchromosomal dynamics during meiotic prophase.
Proceedings of the National Academy of Sciences of the United States of America
2022; 119 (12): e2115883119
Abstract
SignificanceEssential for sexual reproduction, meiosis is a specialized cell division required for the production of haploid gametes. Critical to this process are the pairing, recombination, and segregation of homologous chromosomes (homologs). While pairing and recombination are linked, it is not known how many linkages are sufficient to hold homologs in proximity. Here, we reveal that random diffusion and the placement of a small number of linkages are sufficient to establish the apparent "pairing" of homologs. We also show that colocalization between any two loci is more dynamic than anticipated. Our study provides observations of live interchromosomal dynamics during meiosis and illustrates the power of combining single-cell measurements with theoretical polymer modeling.
View details for DOI 10.1073/pnas.2115883119
View details for PubMedID 35302885
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Statistical behavior of nonequilibrium and living biological systems subjected to active and thermal fluctuations.
Physical review. E
2022; 105 (1-1): 014415
Abstract
We present a path-integral formulation of the motion of a particle subjected to fluctuating active and thermal forces. This general framework predicts the statistical behavior associated with the stochastic trajectories of the particle, accounting for all possible realizations of Brownian and active forces, over an arbitrary potential landscape. Temporal correlations in the active forces result in non-Markovian statistics, necessitating the inclusion of a fixed active-force value at specified times within the statistical treatment. We specialize our theory to that of exponentially correlated active forces for a particle in a harmonic potential. We find the exact results for the statistical distributions for the initial position of the particle, accounting for the impact of the correlated active forces at all times prior to the initial time. Our theory is then used to find the two-point distribution for the active Brownian particle, which governs the joint probability that a particle begins and ends at specified locations. Analyses of the active Brownian statistics demonstrate that the impact of active forces can be interpreted through a time-dependent temperature whose influence depends on the competition of timescales of the active-force correlation and the relaxation time of the particle in the harmonic potential. The general results presented in this work are transferable to a broad range of nonequilibrium systems with active and Brownian motion, and the time-dependent temperature serves as a governing principle to describe the competition of timescales associated with active forces and internal relaxation processes.
View details for DOI 10.1103/PhysRevE.105.014415
View details for PubMedID 35193230
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Free Energy and Dynamics of Annihilation of Topological Defects in Nanoconfined DNA
MACROMOLECULES
2021; 54 (20): 9268-9279
View details for DOI 10.1021/acs.macromol.1c01164
View details for Web of Science ID 000711772900003
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Microrheology reveals simultaneous cell-mediated matrix stiffening and fluidization that underlie breast cancer invasion.
Science advances
2021; 7 (8)
Abstract
Living tissues embody a unique class of hybrid materials in which active and thermal forces are inextricably linked. Mechanical characterization of tissues demands descriptors that respect this hybrid nature. In this work, we develop a microrheology-based force spectrum analysis (FSA) technique to dissect the active and passive fluctuations of the extracellular matrix (ECM) in three-dimensional (3D) cell culture models. In two different stromal models and a 3D breast cancer spheroid model, our FSA reveals emergent hybrid dynamics that involve both high-frequency stress stiffening and low-frequency fluidization of the ECM. We show that this is a general consequence of nonlinear coupling between active forces and the frequency-dependent viscoelasticity of stress-stiffening networks. In 3D breast cancer spheroids, this dual active stiffening and fluidization is tightly connected with invasion. Our results suggest a mechanism whereby breast cancer cells reconcile the seemingly contradictory requirements for both tension and malleability in the ECM during invasion.
View details for DOI 10.1126/sciadv.abe1969
View details for PubMedID 33597244
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Dynamic light scattering microrheology for soft and living materials.
Soft matter
2021
Abstract
We present a method for using dynamic light scattering in the single-scattering limit to measure the viscoelastic moduli of soft materials. This microrheology technique only requires a small sample volume of 12 muL to measure up to six decades in time of rheological behavior. We demonstrate the use of dynamic light scattering microrheology (DLSmuR) on a variety of soft materials, including dilute polymer solutions, covalently-crosslinked polymer gels, and active, biological fluids. In this work, we detail the procedure for applying the technique to new materials and discuss the critical considerations for implementing the technique, including a custom analysis script for analyzing data output. We focus on the advantages of applying DLSmuR to biologically relevant materials: breast cancer cells encapsulated in a collagen gel and cystic fibrosis sputum. DLSmuR is an easy, efficient, and economical rheological technique that can guide the design of new polymeric materials and facilitate the understanding of the underlying physics governing behavior of naturally derived materials.
View details for DOI 10.1039/d0sm01597k
View details for PubMedID 33427280
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Impact of chromosomal organization on epigenetic drift and domain stability revealed by physics-based simulations.
Biophysical journal
2021
Abstract
We examine the relationship between the size of domains of epigenetic marks and the stability of those domains using our theoretical model that captures the physical mechanisms governing the maintenance of epigenetic modifications. We focus our study on histone H3 lysine-9 trimethylation (H3K9me3), one of the most common and consequential epigenetic marks with roles in chromatin compaction and gene repression. Our model combines the effects of methyl spreading by methyltransferases and chromatin segregation into heterochromatin and euchromatin due to preferential Heterochromatin Protein 1 (HP1) binding. Our model indicates that, while large methylated domains are passed successfully from one chromatin generation to the next, small alterations to the methylation sequence are not maintained during chromatin replication. Using our predictive model, we investigate the size required for an epigenetic domain to persist over chromatin generations while surrounded by a much larger domain of opposite methylation and compaction state. We find that there is a critical size threshold in the hundreds-of-nucleosomes scale above which an epigenetic domain will be reliably maintained over generations. The precise size of the threshold differs for heterochromatic and euchromatic domains. Our results are consistent with natural alterations to the epigenetic sequence occurring during embryonic development and due to age-related epigenetic drift.
View details for DOI 10.1016/j.bpj.2021.10.019
View details for PubMedID 34687722
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Lipid Nanodiscs via Ordered Copolymers
CHEM
2020; 6 (10): 2782–95
View details for DOI 10.1016/j.chempr.2020.08.004
View details for Web of Science ID 000580615300022
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Erratum: "Polymer physics across scales: Modeling the multiscale behavior of functional soft materials and biological systems" [J. Chem. Phys. 151, 230902 (2019)].
The Journal of chemical physics
2020; 153 (9): 099901
View details for DOI 10.1063/5.0023713
View details for PubMedID 32891105
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Systematic Approach toward Accurate and Efficient DNA Sequencing via Nanoconfinement
ACS MACRO LETTERS
2020; 9 (8): 1184–91
View details for DOI 10.1021/acsmacrolett.0c00423
View details for Web of Science ID 000563026400016
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Physical modeling of the heritability and maintenance of epigenetic modifications.
Proceedings of the National Academy of Sciences of the United States of America
2020
Abstract
We develop a predictive theoretical model of the physical mechanisms that govern the heritability and maintenance of epigenetic modifications. This model focuses on a particular modification, methylation of lysine-9 of histone H3 (H3K9), which is one of the most representative and critical epigenetic marks that affects chromatin organization and gene expression. Our model combines the effect of segregation and compaction on chromosomal organization with the effect of the interaction between proteins that compact the chromatin (heterochromatin protein 1) and the methyltransferases that affect methyl spreading. Our chromatin model demonstrates that a block of H3K9 methylations in the epigenetic sequence determines the compaction state at any particular location in the chromatin. Using our predictive model for chromatin compaction, we develop a methylation model to address the reestablishment of the methylation sequence following DNA replication. Our model reliably maintains methylation over generations, thereby establishing the robustness of the epigenetic code.
View details for DOI 10.1073/pnas.1920499117
View details for PubMedID 32778583
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Brachiation of a polymer chain in the presence of a dynamic network
PHYSICAL REVIEW E
2020; 102 (2)
View details for DOI 10.1103/PhysRevE.102.020501
View details for Web of Science ID 000557932200004
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Brachiation of a polymer chain in the presence of a dynamic network.
Physical review. E
2020; 102 (2-1): 020501
Abstract
The viscoelastic behavior of a physically crosslinked gel involves a spectrum of molecular relaxation processes, which at the single-chain level involve the chain undergoing transient hand-to-hand motion through the network. We develop a self-consistent theory for describing transiently associating polymer solutions that captures these complex dynamics. A single polymer chain transiently binds to a viscoelastic background that represents the polymer network formed by surrounding polymer chains. The viscoelastic background is described in the equation of motion as a memory kernel, which is self-consistently determined based on the predicted rheological behavior from the chain itself. The solution to the memory kernel is translated into rheological predictions of the complex modulus over a wide range of frequencies to capture the time-dependent behavior of a physical gel. Using the loss tangent predictions, a phase diagram is shown for the sol-gel transition of polymers with dynamic association affinities. This theory provides a predictive, molecular-level framework for the design of associating gels and supramolecular assemblies with targeted rheological properties.
View details for DOI 10.1103/PhysRevE.102.020501
View details for PubMedID 32942387
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Leading Edge Maintenance in Migrating Neutrophil-Like HL-60 Cells is an Emergent Property of Branched Actin Growth
CELL PRESS. 2020: 603A
View details for Web of Science ID 000513023204019
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Chromatin Compaction Leads to a Preference forPeripheral Heterochromatin.
Biophysical journal
2020
Abstract
A layer of dense heterochromatin is found at the periphery of the nucleus. Because this peripheral heterochromatin functions as a repressive phase, mechanisms that relocate genes to the periphery play an important role in regulating transcription. Using Monte Carlo simulations, we show that an interaction that attracts euchromatin and heterochromatin equally to the nuclear envelope will still preferentially locate heterochromatin to the nuclear periphery. This observation considerably broadens the class of possible interactions that result in peripheral positioning to include boundary interactions that either weakly attract all chromatin or strongly bind to a randomly chosen 0.05% of nucleosomes. The key distinguishing feature of heterochromatin is its high chromatin density with respect to euchromatin. In our model, this densification is caused by heterochromatin protein 1's preferential binding to histone H3 tails with a methylated lysine at the ninth residue, a hallmark of heterochromatin. We find that a global rearrangement of chromatin to place heterochromatin at the nuclear periphery can be accomplished by attaching a small subset of loci, even if these loci are uncorrelated with heterochromatin. Hence, factors that densify chromatin determine which genomic regions condense to form peripheral heterochromatin.
View details for DOI 10.1016/j.bpj.2020.01.034
View details for PubMedID 32097622
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Chromosome Structural Mechanics Dictates the Local Spreading of Epigenetic Marks.
Biophysical journal
2020
Abstract
We present a theoretical model that demonstrates the integral role chromosome organization and structural mechanics play in the spreading of histone modifications involved in epigenetic regulation. Our model shows that heterogeneous nucleosome positioning, and the resulting position-dependent mechanical properties, must be included to reproduce several qualitative features of experimental data of histone methylation spreading around an artificially induced "nucleation site." We show that our model recreates both the extent of spreading and the presence of a subdominant peak upstream of the transcription start site. Our model indicates that the spreading of epigenetic modifications is sensitive to heterogeneity in chromatin organization and the resulting variability in the chromatin's mechanical properties, suggesting that nucleosome spacing can directly control the conferral of epigenetic marks by modifying the structural mechanics of the chromosome. It further illustrates how the physical organization of the DNA polymer may play a significant role in re-establishing the epigenetic code upon cell division.
View details for DOI 10.1016/j.bpj.2020.08.039
View details for PubMedID 33010237
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Polymer physics across scales: Modeling the multiscale behavior of functional soft materials and biological systems.
The Journal of chemical physics
2019; 151 (23): 230902
Abstract
Polymeric materials are ubiquitous in our daily lives, and they play a significant role in many technological applications. The general predictive framework for the behavior of soft polymeric materials can be divided into two vastly different approaches. Highly coarse-grained models capture polymers as flexible random walks, resulting in general predictions of physical behavior but lack chemical specificity. Detailed atomistic models contain molecular detail but are frequently computationally intractable for exhaustive materials discovery. In this perspective, we discuss theoretical models that successfully bridge these disparate approaches. We identify intermediate-scale physical models that are amenable to theoretical analyses while containing sufficient granular detail to capture a range of molecular-level processes. We then provide several problems in materials engineering and biological physics where multiscale physics is essential in their behavior.
View details for DOI 10.1063/1.5126852
View details for PubMedID 31864250
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Impact of Liquid-Crystalline Chain Alignment on Charge Transport in Conducting Polymers
MACROMOLECULES
2019; 52 (22): 8932–39
View details for DOI 10.1021/acs.macromol.9b01729
View details for Web of Science ID 000500039300040
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Geometrical Heterogeneity Dominates Thermal Fluctuations in Facilitating Chromatin Contacts.
Physical review letters
2019; 123 (20): 208103
Abstract
Within a living cell, the myriad of proteins that bind DNA introduce heterogeneously spaced kinks into an otherwise semiflexible DNA double helix. To investigate the effects of heterogeneous nucleosome binding on chromatin organization, we extend the wormlike chain model to include statistically spaced, rigid kinks. On timescales where nucleosome positions are fixed, we find that the probability of chromatin loop formation can vary by up to six orders of magnitude between two sets of nucleosome positions drawn from the same distribution. On longer timescales, we show that continuous rerandomization due to nucleosome turnover results in chromatin tracing out an effective WLC with a dramatically smaller Kuhn length than bare DNA. Together, these observations demonstrate that nucleosome spacing acts as the primary source of the structural heterogeneity that dominates local and global chromatin organization.
View details for DOI 10.1103/PhysRevLett.123.208103
View details for PubMedID 31809067
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Geometrical Heterogeneity Dominates Thermal Fluctuations in Facilitating Chromatin Contacts
PHYSICAL REVIEW LETTERS
2019; 123 (20)
View details for DOI 10.1103/PhysRevLett.123.208103
View details for Web of Science ID 000496929700021
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Physical modeling of the spreading of epigenetic modifications through transient DNA looping
JOURNAL OF PHYSICS A-MATHEMATICAL AND THEORETICAL
2019; 52 (43)
View details for DOI 10.1088/1751-8121/ab41d2
View details for Web of Science ID 000518774900001
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Transient Anomalous Diffusion in a Heterogeneous Environment
FRONTIERS IN PHYSICS
2019; 7
View details for DOI 10.3389/fphy.2019.00119
View details for Web of Science ID 000483538200001
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A fluorogenic array for temporally unlimited single-molecule tracking
NATURE CHEMICAL BIOLOGY
2019; 15 (4): 401-+
View details for DOI 10.1038/s41589-019-0241-6
View details for Web of Science ID 000461952900018
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A fluorogenic array for temporally unlimited single-molecule tracking.
Nature chemical biology
2019
Abstract
We describe three optical tags, ArrayG, ArrayD and ArrayG/N, for intracellular tracking of single molecules over milliseconds to hours. ArrayG is a fluorogenic tag composed of a green fluorescent protein-nanobody array and monomeric wild-type green fluorescent protein binders that are initially dim but brighten ~26-fold on binding with the array. By balancing the rates of binder production, photobleaching and stochastic binder exchange, we achieve temporally unlimited tracking of single molecules. High-speed tracking of ArrayG-tagged kinesins and integrins for thousands of frames reveals novel dynamical features. Tracking of single histones at 0.5Hz for>1hour with the import competent ArrayG/N tag shows that chromosomal loci behave as Rouse polymers with visco-elastic memory and exhibit a non-Gaussian displacement distribution. ArrayD, based on a dihydrofolate reductase nanobody array and dihydrofolate reductase-fluorophore binder, enables dual-color imaging. The arrays combine brightness, fluorogenicity, fluorescence replenishment and extended fluorophore choice, opening new avenues for tracking single molecules in living cells.
View details for PubMedID 30858596
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Bottom-up modeling of chromatin segregation due to epigenetic modifications.
Proceedings of the National Academy of Sciences of the United States of America
2018
Abstract
We use a chromosome-scale simulation to show that the preferential binding of heterochromatin protein 1 (HP1) to regions high in histone methylation (specifically H3K9me3) results in phase segregation and reproduces features of the observed Hi-C contact map. Specifically, we perform Monte Carlo simulations with one computational bead per nucleosome and an H3K9me3 pattern based on published ChIP-seq signals. We implement a binding model in which HP1 preferentially binds to trimethylated histone tails and then oligomerizes to bridge together nucleosomes. We observe a phase reminiscent of heterochromatin-dense and high in H3K9me3-and another reminiscent of euchromatin-less dense and lacking H3K9me3. This segregation results in a plaid contact probability map that matches the general shape and position of published Hi-C data. Analysis suggests that a roughly 20-kb segment of H3K9me3 enrichment is required to drive segregation into the heterochromatic phase.
View details for PubMedID 30478042
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Active DNA Olympic Hydrogels Driven by Topoisomerase Activity.
Physical review letters
2018; 121 (14): 148001
Abstract
Biological systems are equipped with a diverse repertoire of proteins that regulate DNA topology with precision that is beyond the reach of conventional polymer chemistry. Here, we harness the unique properties of topoisomerases to synthesize Olympic hydrogels formed by topologically interlinked DNA rings. Using dynamic light scattering microrheology to probe the viscoelasticity of DNA topological networks, we show that topoisomerase II enables the facile preparation of active, adenosine triphosphate-driven Olympic hydrogels that can be switched between liquid and solid states on demand. Our results provide a versatile system for engineering switchable topological materials that may be broadly leveraged to model the impact of topological constraints and active dynamics in the physics of chromosomes and other polymeric materials.
View details for DOI 10.1103/PhysRevLett.121.148001
View details for PubMedID 30339454
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Active DNA Olympic Hydrogels Driven by Topoisomerase Activity
PHYSICAL REVIEW LETTERS
2018; 121 (14)
View details for DOI 10.1103/PhysRevLett.121.148001
View details for Web of Science ID 000446138000014
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Strong disorder leads to scale invariance in complex biological systems
PHYSICAL REVIEW E
2018; 97 (6): 062410
Abstract
Despite the innate complexity of the cell, emergent scale-invariant behavior is observed in many biological systems. We investigate one example of this phenomenon: the dynamics of large complexes in the bacterial cytoplasm. The observed dynamics of these complexes is scale invariant in three measures of dynamics: mean-squared displacement (MSD), velocity autocorrelation function, and the step-size distribution. To investigate the physical mechanism for this emergent scale invariance, we explore minimal models in which mobility is modeled as diffusion on a rough free-energy landscape in one dimension. We discover that all three scale-invariant characteristics emerge generically in the strong disorder limit. (Strong disorder is defined by the divergence of the ensemble-averaged hop time between lattice sites.) In particular, we demonstrate how the scale invariance of the relative step-size distribution can be understood from the perspective of extreme-value theory in statistics (EVT). We show that the Gumbel scale parameter is simply related to the MSD scaling parameter. The EVT mechanism of scale invariance is expected to be generic to strongly disordered systems and therefore a powerful tool for the analysis of other systems in biology and beyond.
View details for PubMedID 30011517
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Thermodynamic Model of Solvent Effects in Semiflexible Diblock and Random Copolymer Assembly
MACROMOLECULES
2018; 51 (11): 4167–77
View details for DOI 10.1021/acs.macromol.8b00172
View details for Web of Science ID 000435417800027
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Polymer Semiflexibility Induces Nonuniversal Phase Transitions in Diblock Copolymers
PHYSICAL REVIEW LETTERS
2018; 120 (6): 067802
Abstract
The order-disorder phase transition and the associated phase diagrams of semiflexible diblock copolymers are investigated using the wormlike chain model, incorporating concentration fluctuations. The free energy up to quartic order in concentration fluctuations is developed with chain-rigidity-dependent coefficients, evaluated using our exact results for the wormlike chain model, and a one-loop renormalization treatment is used to account for fluctuation effects. The chain length N and the monomer aspect ratio α directly control the strength of immiscibility (defined by the Flory-Huggins parameter χ) at the order-disorder transition and the resulting microstructures at different chemical compositions f_{A}. When monomers are infinitely thin (i.e., large aspect ratio α), the finite chain length N lowers the χN at the phase transition. However, fluctuation effects become important when chains have a finite radius, and a decrease in the chain length N elevates the χN at the phase transition. Phase diagrams of diblock copolymers over a wide range of N and α are calculated based on our fluctuation theory. We find that both finite N and α enhance the stability of the lamellar phase above the order-disorder transition. Our results demonstrate that polymer semiflexibility plays a dramatic role in the phase behavior, even for large chain lengths (e.g., N≈100).
View details for PubMedID 29481283
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Stability on the Edge: Probing the Biophysical Mechanisms of Polarity Maintenance in Motile Cells
CELL PRESS. 2018: 648A–649A
View details for Web of Science ID 000430563300235
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Long-Range Structural Changes in the Meiotic Nucleus Revealed by Changes in Stress Communication Along the Chromosome
CELL PRESS. 2018: 30A
View details for Web of Science ID 000429315800158
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A Polymer Physics Model for Epigenetic Control of Chromatin Compaction
CELL PRESS. 2018: 563A
View details for Web of Science ID 000430563200567
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Physical Modeling of the Spreading and Maintenance of Epigenetic Modifications through DNA Looping and Condensation
CELL PRESS. 2018: 583A
View details for Web of Science ID 000430563200673
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Interrogating Cell-Mediated Remodeling of the Extracellular Matrix by Dynamic Light Scattering Microrheology
CELL PRESS. 2018: 371A–372A
View details for Web of Science ID 000430450000347
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Fluctuation Effects in Semiflexible Diblock Copolymers.
ACS macro letters
2018; 7 (1): 59-64
Abstract
We present a simulation study of the equilibrium thermodynamic behavior of semiflexible diblock copolymer melts. Using discretized wormlike chains and field-theoretic Monte Carlo, we find that concentration fluctuations play a critical role in controlling phase transitions of semiflexible diblock copolymers. Polymer flexibility and aspect ratio control the order-disorder transition Flory-Huggins parameter χODTN. For polymers with low aspect ratios, fluctuations strongly elevate the phase transition χODTN at finite molecular weights. For high aspect-ratio polymers, chain semiflexibility decreases the phase transition χODTN. We find that the simulated phase behavior agrees well with our recently developed fluctuation theory based on wormlike chain configurations and a one-loop treatment of concentration fluctuations.
View details for DOI 10.1021/acsmacrolett.7b00638
View details for PubMedID 35610917
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Biotemplated synthesis of inorganic materials: An emerging paradigm for nanomaterial synthesis inspired by nature
PROGRESS IN MATERIALS SCIENCE
2018; 91: 1–23
View details for DOI 10.1016/j.pmatsci.2017.08.001
View details for Web of Science ID 000415780300001
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Fluctuation Effects in Semiflexible Diblock Copolymers
ACS MACRO LETTERS
2018; 7 (1): 59–64
View details for DOI 10.1021/acsmacrolett.7b00638
View details for Web of Science ID 000423016200011
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Dynamic Light Scattering Microrheology Reveals Multiscale Viscoelasticity of Polymer Gels and Precious Biological Materials
ACS CENTRAL SCIENCE
2017; 3 (12): 1294–1303
Abstract
The development of experimental techniques capable of probing the viscoelasticity of soft materials over a broad range of time scales is essential to uncovering the physics that governs their behavior. In this work, we develop a microrheology technique that requires only 12 μL of sample and is capable of resolving dynamic behavior ranging in time scales from 10-6 to 10 s. Our approach, based on dynamic light scattering in the single-scattering limit, enables the study of polymer gels and other soft materials over a vastly larger hierarchy of time scales than macrorheology measurements. Our technique captures the viscoelastic modulus of polymer hydrogels with a broad range of stiffnesses from 10 to 104 Pa. We harness these capabilities to capture hierarchical molecular relaxations in DNA and to study the rheology of precious biological materials that are impractical for macrorheology measurements, including decellularized extracellular matrices and intestinal mucus. The use of a commercially available benchtop setup that is already available to a variety of soft matter researchers renders microrheology measurements accessible to a broader range of users than existing techniques, with the potential to reveal the physics that underlies complex polymer hydrogels and biological materials.
View details for PubMedID 29296670
View details for PubMedCentralID PMC5746858
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Field-theoretic simulations of random copolymers with structural rigidity
SOFT MATTER
2017; 13 (15): 2760-2772
Abstract
Copolymers play an important role in a range of soft-materials applications and biological phenomena. Prevalent works on block copolymer phase behavior use flexible chain models and incorporate interactions using a mean-field approximation. However, when phase separation takes place on length scales comparable to a few monomers, the structural rigidity of the monomers becomes important. In addition, concentration fluctuations become significant at short length scales, rendering the mean-field approximation invalid. In this work, we use simulation to address the role of finite monomer rigidity and concentration fluctuations in microphase segregation of random copolymers. Using a field-theoretic Monte-Carlo simulation of semiflexible polymers with random chemical sequences, we generate phase diagrams for random copolymers. We find that the melt morphology of random copolymers strongly depends on chain flexibility and chemical sequence correlation. Chemically anti-correlated copolymers undergo first-order phase transitions to local lamellar structures. With increasing degree of chemical correlation, this first-order phase transition is softened, and melts form microphases with irregular shaped domains. Our simulations in the homogeneous phase exhibit agreement with the density-density correlation from mean-field theory. However, conditions near a phase transition result in deviations between simulation and mean-field theory for the density-density correlation and the critical wavemode. Chain rigidity and sequence randomness lead to frustration in the segregated phase, introducing heterogeneity in the resulting morphologies.
View details for DOI 10.1039/c7sm00164a
View details for Web of Science ID 000399386000005
View details for PubMedID 28338151
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Buckling a Semiflexible Polymer Chain under Compression.
Polymers
2017; 9 (3)
Abstract
Instability and structural transitions arise in many important problems involving dynamics at molecular length scales. Buckling of an elastic rod under a compressive load offers a useful general picture of such a transition. However, the existing theoretical description of buckling is applicable in the load response of macroscopic structures, only when fluctuations can be neglected, whereas membranes, polymer brushes, filaments, and macromolecular chains undergo considerable Brownian fluctuations. We analyze here the buckling of a fluctuating semiflexible polymer experiencing a compressive load. Previous works rely on approximations to the polymer statistics, resulting in a range of predictions for the buckling transition that disagree on whether fluctuations elevate or depress the critical buckling force. In contrast, our theory exploits exact results for the statistical behavior of the worm-like chain model yielding unambiguous predictions about the buckling conditions and nature of the buckling transition. We find that a fluctuating polymer under compressive load requires a larger force to buckle than an elastic rod in the absence of fluctuations. The nature of the buckling transition exhibits a marked change from being distinctly second order in the absence of fluctuations to being a more gradual, compliant transition in the presence of fluctuations. We analyze the thermodynamic contributions throughout the buckling transition to demonstrate that the chain entropy favors the extended state over the buckled state, providing a thermodynamic justification of the elevated buckling force.
View details for DOI 10.3390/polym9030099
View details for PubMedID 30970780
View details for PubMedCentralID PMC6432112
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Buckling a Semiflexible Polymer Chain under Compression
POLYMERS
2017; 9 (3)
View details for DOI 10.3390/polym9030099
View details for Web of Science ID 000397231100023
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Crowding and hopping in a protein's diffusive transport on DNA
JOURNAL OF PHYSICS A-MATHEMATICAL AND THEORETICAL
2017; 50 (7)
View details for DOI 10.1088/1751-8121/aa53ee
View details for Web of Science ID 000393972100004
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Cytoplasmic RNA-Protein Particles Exhibit Non-Gaussian Subdiffusive Behavior.
Biophysical journal
2017; 112 (3): 532-542
Abstract
The cellular cytoplasm is a complex, heterogeneous environment (both spatially and temporally) that exhibits viscoelastic behavior. To further develop our quantitative insight into cellular transport, we analyze data sets of mRNA molecules fluorescently labeled with MS2-GFP tracked in real time in live Escherichia coli and Saccharomyces cerevisiae cells. As shown previously, these RNA-protein particles exhibit subdiffusive behavior that is viscoelastic in its origin. Examining the ensemble of particle displacements reveals a Laplace distribution at all observed timescales rather than the Gaussian distribution predicted by the central limit theorem. This ensemble non-Gaussian behavior is caused by a combination of an exponential distribution in the time-averaged diffusivities and non-Gaussian behavior of individual trajectories. We show that the non-Gaussian behavior is a consequence of significant heterogeneity between trajectories and dynamic heterogeneity along single trajectories. Informed by theory and simulation, our work provides an in-depth analysis of the complex diffusive behavior of RNA-protein particles in live cells.
View details for DOI 10.1016/j.bpj.2016.11.3208
View details for PubMedID 28088300
View details for PubMedCentralID PMC5300785
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Anomalous Charge Transport in Conjugated Polymers Reveals Underlying Mechanisms of Trapping and Percolation
ACS CENTRAL SCIENCE
2016; 2 (12): 910-915
Abstract
While transport in conjugated polymers has many similarities to that in crystalline inorganic materials, several key differences reveal the unique relationship between the morphology of polymer films and the charge mobility. We develop a model that directly incorporates the molecular properties of the polymer film and correctly predicts these unique transport features. At low degree of polymerization, the increase of the mobility with the polymer chain length reveals trapping at chain ends, and saturation of the mobility at high degree of polymerization results from conformational traps within the chains. Similarly, the inverse field dependence of the mobility reveals that transport on single polymer chains is characterized by the ability of the charge to navigate around kinks and loops in the chain. These insights emphasize the connection between the polymer conformations and the transport and thereby offer a route to designing improved device morphologies through molecular design and materials processing.
View details for DOI 10.1021/acscentsci.6b00251
View details for Web of Science ID 000390865300008
View details for PubMedID 28058280
View details for PubMedCentralID PMC5200932
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Large-Scale Conformational Transitions in Supercoiled DNA Revealed by Coarse-Grained Simulation
BIOPHYSICAL JOURNAL
2016; 111 (7): 1339-1349
Abstract
Topological constraints, such as those associated with DNA supercoiling, play an integral role in genomic regulation and organization in living systems. However, physical understanding of the principles that underlie DNA organization at biologically relevant length scales remains a formidable challenge. We develop a coarse-grained simulation approach for predicting equilibrium conformations of supercoiled DNA. Our methodology enables the study of supercoiled DNA molecules at greater length scales and supercoiling densities than previously explored by simulation. With this approach, we study the conformational transitions that arise due to supercoiling across the full range of supercoiling densities that are commonly explored by living systems. Simulations of ring DNA molecules with lengths at the scale of topological domains in the Escherichia coli chromosome (∼10 kilobases) reveal large-scale conformational transitions elicited by supercoiling. The conformational transitions result in three supercoiling conformational regimes that are governed by a competition among chiral coils, extended plectonemes, and branched hyper-supercoils. These results capture the nonmonotonic relationship of size versus degree of supercoiling observed in experimental sedimentation studies of supercoiled DNA, and our results provide a physical explanation of the conformational transitions underlying this behavior. The length scales and supercoiling regimes investigated here coincide with those relevant to transcription-coupled remodeling of supercoiled topological domains, and we discuss possible implications of these findings in terms of the interplay between transcription and topology in bacterial chromosome organization.
View details for DOI 10.1016/j.bpj.2016.07.045
View details for Web of Science ID 000385471500002
View details for PubMedID 27705758
View details for PubMedCentralID PMC5052444
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Eliminating Fitting from the Modeling of Biological Processes.
ACS central science
2016; 2 (9): 584-585
View details for PubMedID 27725953
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Impact of Conformational and Chemical Correlations on Microphase Segregation in Random Copolymers
MACROMOLECULES
2016; 49 (11): 4358-4368
View details for DOI 10.1021/acs.macromol.5b02639
View details for Web of Science ID 000378016200037
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Potential for measurement of the distribution of DNA folds in complex environments using Correlated X-ray Scattering
MODERN PHYSICS LETTERS B
2016; 30 (8)
View details for DOI 10.1142/S0217984916501177
View details for Web of Science ID 000373991200017
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Physical Modeling of Dynamic Coupling between Chromosomal Loci.
Biophysical journal
2016; 110 (2): 338-347
Abstract
The motion of chromosomal DNA is essential to many biological processes, including segregation, transcriptional regulation, recombination, and packaging. Physical understanding of these processes would be dramatically enhanced through predictive, quantitative modeling of chromosome dynamics of multiple loci. Using a polymer dynamics framework, we develop a prediction for the correlation in the velocities of two loci on a single chromosome or otherwise connected by chromatin. These predictions reveal that the signature of correlated motion between two loci can be identified by varying the lag time between locus position measurements. In general, this theory predicts that as the lag time interval increases, the dual-loci dynamic behavior transitions from being completely uncorrelated to behaving as an effective single locus. This transition corresponds to the timescale of the stress communication between loci through the intervening segment. This relatively simple framework makes quantitative predictions based on a single timescale fit parameter that can be directly compared to the in vivo motion of fluorescently labeled chromosome loci. Furthermore, this theoretical framework enables the detection of dynamically coupled chromosome regions from the signature of their correlated motion.
View details for DOI 10.1016/j.bpj.2015.11.3520
View details for PubMedID 26789757
View details for PubMedCentralID PMC4724634
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Physical Modeling of Dynamic Coupling between Chromosomal Loci
BIOPHYSICAL JOURNAL
2016; 110 (2): 338-347
View details for DOI 10.1016/j.bpj.2015.11.3520
View details for Web of Science ID 000368354700008
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Potential for measurement of the distribution of DNA folds in complex environments using Correlated X-ray Scattering.
Modern physics letters. B, Condensed matter physics, statistical physics, applied physics
2016; 30 (8)
Abstract
In vivo chromosomal behavior is dictated by the organization of genomic DNA at length scales ranging from nanometers to microns. At these disparate scales, the DNA conformation is influenced by a range of proteins that package, twist and disentangle the DNA double helix, leading to a complex hierarchical structure that remains undetermined. Thus, there is a critical need for methods of structural characterization of DNA that can accommodate complex environmental conditions over biologically relevant length scales. Based on multiscale molecular simulations, we report on the possibility of measuring supercoiling in complex environments using angular correlations of scattered X-rays resulting from X-ray free electron laser (xFEL) experiments. We recently demonstrated the observation of structural detail for solutions of randomly oriented metallic nanoparticles [D. Mendez et al., Philos. Trans. R. Soc. B360 (2014) 20130315]. Here, we argue, based on simulations, that correlated X-ray scattering (CXS) has the potential for measuring the distribution of DNA folds in complex environments, on the scale of a few persistence lengths.
View details for PubMedID 27127310
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Interplay of Protein Binding Interactions, DNA Mechanics, and Entropy in DNA Looping Kinetics
BIOPHYSICAL JOURNAL
2015; 109 (3): 618-629
Abstract
DNA looping plays a key role in many fundamental biological processes, including gene regulation, recombination, and chromosomal organization. The looping of DNA is often mediated by proteins whose structural features and physical interactions can alter the length scale at which the looping occurs. Looping and unlooping processes are controlled by thermodynamic contributions associated with mechanical deformation of the DNA strand and entropy arising from thermal fluctuations of the conformation. To determine how these confounding effects influence DNA looping and unlooping kinetics, we present a theoretical model that incorporates the role of the protein interactions, DNA mechanics, and conformational entropy. We show that for shorter DNA strands the interaction distance affects the transition state, resulting in a complex relationship between the looped and unlooped state lifetimes and the physical properties of the looped DNA. We explore the range of behaviors that arise with varying interaction distance and DNA length. These results demonstrate how DNA deformation and entropy dictate the scaling of the looping and unlooping kinetics versus the J-factor, establishing the connection between kinetic and equilibrium behaviors. Our results show how the twist-and-bend elasticity of the DNA chain modulates the kinetics and how the influence of the interaction distance fades away at intermediate to longer chain lengths, in agreement with previous scaling predictions.
View details for DOI 10.1016/j.bpj.2015.06.054
View details for Web of Science ID 000359180400018
View details for PubMedID 26244743
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Percolation, Tie-Molecules, and the Microstructural Determinants of Charge Transport in Semicrystalline Conjugated Polymers
ACS MACRO LETTERS
2015; 4 (7): 708-712
View details for DOI 10.1021/acsmacrolett.5b00314
View details for Web of Science ID 000358560100011
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Thermodynamic model of heterochromatin formation through epigenetic regulation.
Journal of physics. Condensed matter : an Institute of Physics journal
2015; 27 (6): 064109-?
Abstract
Gene regulation in eukaryotes requires the segregation of silenced genomic regions into densely packed heterochromatin, leaving the active genes in euchromatin regions more accessible. We introduce a model that connects the presence of epigenetically inherited histone marks, methylation at histone 3 lysine-9, to the physical compaction of chromatin fibers via the binding of heterochromatin protein 1 (HP1). Our model demonstrates some of the key physical features that are necessary to explain experimental observations. In particular, we demonstrate that strong cooperative interactions among the HP1 proteins are necessary to see the phase segregation of heterochromatin and euchromatin regions. We also explore how the cell can use the concentration of HP1 to control condensation and under what circumstances there is a threshold of methylation over which the fibers will compact. Finally, we consider how different potential in vivo fiber structures as well as the flexibility of the histone 3 tail can affect the bridging of HP1. Many of the observations that we make about the HP1 system are guided by general thermodynamics principles and thus could play a role in other DNA organizational processes such as the binding of linker histones.
View details for DOI 10.1088/0953-8984/27/6/064109
View details for PubMedID 25563699
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Physical Modeling of Chromosome Segregation in Escherichia coli Reveals Impact of Force and DNA Relaxation.
Biophysical journal
2015; 108 (1): 146-153
Abstract
The physical mechanism by which Escherichia coli segregates copies of its chromosome for partitioning into daughter cells is unknown, partly due to the difficulty in interpreting the complex dynamic behavior during segregation. Analysis of previous chromosome segregation measurements in E. coli demonstrates that the origin of replication exhibits processive motion with a mean displacement that scales as t(0.32). In this work, we develop a model for segregation of chromosomal DNA as a Rouse polymer in a viscoelastic medium with a force applied to a single monomer. Our model demonstrates that the observed power-law scaling of the mean displacement and the behavior of the velocity autocorrelation function is captured by accounting for the relaxation of the polymer chain and the viscoelastic environment. We show that the ratio of the mean displacement to the variance of the displacement during segregation events is a critical metric that eliminates the compounding effects of polymer and medium dynamics and provides the segregation force. We calculate the force of oriC segregation in E. coli to be ∼0.49 pN.
View details for DOI 10.1016/j.bpj.2014.10.074
View details for PubMedID 25564861
View details for PubMedCentralID PMC4286603
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Membrane indentation triggers clathrin lattice reorganization and fluidization
SOFT MATTER
2015; 11 (3): 439-448
Abstract
Clathrin-mediated endocytosis involves the coordinated assembly of clathrin cages around membrane indentations, necessitating fluid-like reorganization followed by solid-like stabilization. This apparent duality in clathrin's in vivo behavior provides some indication that the physical interactions between clathrin triskelia and the membrane effect a local response that triggers fluid-solid transformations within the clathrin lattice. We develop a computational model to study the response of clathrin protein lattices to spherical deformations of the underlying flexible membrane. These deformations are similar to the shapes assumed during intracellular trafficking of nanoparticles. Through Monte Carlo simulations of clathrin-on-membrane systems, we observe that these membrane indentations give rise to a greater than normal defect density within the overlaid clathrin lattice. In many cases, the bulk surrounding lattice remains in a crystalline phase, and the extra defects are localized to the regions of large curvature. This can be explained by the fact that the in-plane elastic stress in the clathrin lattice are reduced by coupling defects to highly curved regions. The presence of defects brought about by indentation can result in the fluidization of a lattice that would otherwise be crystalline, resulting in an indentation-driven, defect-mediated phase transition. Altering subunit elasticity or membrane properties is shown to drive a similar transition, and we present phase diagrams that map out the combined effects of these parameters on clathrin lattice properties.
View details for DOI 10.1039/c4sm01650e
View details for Web of Science ID 000346911600002
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Modulation of DNA loop lifetimes by the free energy of loop formation
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2014; 111 (49): 17396-17401
Abstract
Storage and retrieval of the genetic information in cells is a dynamic process that requires the DNA to undergo dramatic structural rearrangements. DNA looping is a prominent example of such a structural rearrangement that is essential for transcriptional regulation in both prokaryotes and eukaryotes, and the speed of such regulations affects the fitness of individuals. Here, we examine the in vitro looping dynamics of the classic Lac repressor gene-regulatory motif. We show that both loop association and loop dissociation at the DNA-repressor junctions depend on the elastic deformation of the DNA and protein, and that both looping and unlooping rates approximately scale with the looping J factor, which reflects the system's deformation free energy. We explain this observation by transition state theory and model the DNA-protein complex as an effective worm-like chain with twist. We introduce a finite protein-DNA binding interaction length, in competition with the characteristic DNA deformation length scale, as the physical origin of the previously unidentified loop dissociation dynamics observed here, and discuss the robustness of this behavior to perturbations in several polymer parameters.
View details for DOI 10.1073/pnas.1415685111
View details for Web of Science ID 000345921500025
View details for PubMedID 25411314
View details for PubMedCentralID PMC4267329
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Rheology and simulation of 2-dimensional clathrin protein network assembly.
Soft matter
2014; 10 (33): 6219-6227
Abstract
Clathrin is a three-legged protein complex that assembles into lattice structures on the cell membrane and transforms into fullerene-like cages during endocytosis. This dynamic structural flexibility makes clathrin an attractive building block for guided assembly. The assembly dynamics and the mechanical properties of clathrin protein lattices are studied using rheological measurements and theoretical modelling in an effort to better understand two dynamic processes: protein adsorption to the interface and assembly into a network. We find that percolation models for protein network formation are insufficient to describe clathrin network formation, but with Monte Carlo simulations we can describe the dynamics of network formation very well. Insights from this work can be used to design new bio-inspired nano-assembly systems.
View details for DOI 10.1039/c4sm00025k
View details for PubMedID 25012232
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Multiscale dynamics of semiflexible polymers from a universal coarse-graining procedure
PHYSICAL REVIEW E
2014; 90 (1)
View details for DOI 10.1103/PhysRevE.90.013304
View details for Web of Science ID 000341246400010
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Membrane fluctuations destabilize clathrin protein lattice order.
Biophysical journal
2014; 106 (7): 1476-1488
Abstract
We develop a theoretical model of a clathrin protein lattice on a flexible cell membrane. The clathrin subunit is modeled as a three-legged pinwheel with elastic deformation modes and intersubunit binding interactions. The pinwheels are constrained to lie on the surface of an elastic sheet that opposes bending deformation and is subjected to tension. Through Monte Carlo simulations, we predict the equilibrium phase behavior of clathrin lattices at various levels of tension. High membrane tensions, which correspond to suppressed membrane fluctuations, tend to stabilize large, flat crystalline structures similar to plaques that have been observed in vivo on cell membranes that are adhered to rigid surfaces. Low tensions, on the other hand, give rise to disordered, defect-ridden lattices that behave in a fluidlike manner. The principles of two-dimensional melting theory are applied to our model system to further clarify how high tensions can stabilize crystalline order on flexible membranes. These results demonstrate the importance of environmental physical cues in dictating the collective behavior of self-assembled protein structures.
View details for DOI 10.1016/j.bpj.2013.11.4505
View details for PubMedID 24703309
View details for PubMedCentralID PMC3976529
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An in vitro assay for entry into cilia reveals unique properties of the soluble diffusion barrier
JOURNAL OF CELL BIOLOGY
2013; 203 (1): 129-147
Abstract
Specific proteins are concentrated within primary cilia, whereas others remain excluded. To understand the mechanistic basis of entry into cilia, we developed an in vitro assay using cells in which the plasma membrane was permeabilized, but the ciliary membrane was left intact. Using a diffusion-to-capture system and quantitative analysis, we find that proteins >9 nm in diameter (∼100 kD) are restricted from entering cilia, and we confirm these findings in vivo. Interference with the nuclear pore complex (NPC) or the actin cytoskeleton in permeabilized cells demonstrated that the ciliary diffusion barrier is mechanistically distinct from those of the NPC or the axon initial segment. Moreover, applying a mass transport model to this system revealed diffusion coefficients for soluble and membrane proteins within cilia that are compatible with rapid exploration of the ciliary space in the absence of active transport. Our results indicate that large proteins require active transport for entry into cilia but not necessarily for movement inside cilia.
View details for DOI 10.1083/jcb.201212024
View details for Web of Science ID 000325742200013
View details for PubMedID 24100294
View details for PubMedCentralID PMC3798247
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Chain conformations dictate multiscale charge transport phenomena in disordered semiconducting polymers
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2013; 110 (41): 16315-16320
Abstract
Existing models for the electronic properties of conjugated polymers do not capture the spatial arrangement of the disordered macromolecular chains over which charge transport occurs. Here, we present an analytical and computational description in which the morphology of individual polymer chains is dictated by well-known statistical models and the electronic coupling between units is determined using Marcus theory. The multiscale transport of charges in these materials (high mobility at short length scales, low mobility at long length scales) is naturally described with our framework. Additionally, the dependence of mobility with electric field and temperature is explained in terms of conformational variability and spatial correlation. Our model offers a predictive approach to connecting processing conditions with transport behavior.
View details for DOI 10.1073/pnas.1307158110
View details for Web of Science ID 000325395600023
View details for PubMedID 24062459
View details for PubMedCentralID PMC3799354
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Systematic Coarse-Graining of Microscale Polymer Models as Effective Elastic Chains
MACROMOLECULES
2013; 46 (5): 2003-2014
View details for DOI 10.1021/ma302056v
View details for Web of Science ID 000316168600034
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Caulobacter chromosome in vivo configuration matches model predictions for a supercoiled polymer in a cell-like confinement
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2013; 110 (5): 1674-1679
Abstract
We measured the distance between fluorescent-labeled DNA loci of various interloci contour lengths in Caulobacter crescentus swarmer cells to determine the in vivo configuration of the chromosome. For DNA segments less than about 300 kb, the mean interloci distances,
, scale as n(0.22), where n is the contour length, and cell-to-cell distribution of the interloci distance r is a universal function of r/n(0.22) with broad cell-to-cell variability. For DNA segments greater than about 300 kb, the mean interloci distances scale as n, in agreement with previous observations. The 0.22 value of the scaling exponent for short DNA segments is consistent with theoretical predictions for a branched DNA polymer structure. Predictions from Brownian dynamics simulations of the packing of supercoiled DNA polymers in an elongated cell-like confinement are also consistent with a branched DNA structure, and simulated interloci distance distributions predict that confinement leads to "freezing" of the supercoiled configuration. Lateral positions of labeled loci at comparable positions along the length of the cell are strongly correlated when the longitudinal locus positions differ by <0.16 μm. We conclude that the chromosome structure is supercoiled locally and elongated at large length scales and that substantial cell-to-cell variability in the interloci distances indicates that in vivo crowding prevents the chromosome from reaching an equilibrium arrangement. We suggest that the force causing rapid transport of loci remote from the parS centromere to the distal cell pole may arise from the release at the polar region of potential energy within the supercoiled DNA. View details for DOI 10.1073/pnas.1220824110
View details for Web of Science ID 000314558100027
View details for PubMedID 23319648
View details for PubMedCentralID PMC3562846
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Single molecule imaging reveals a major role for diffusion in the exploration of ciliary space by signaling receptors.
eLife
2013; 2
Abstract
The dynamic organization of signaling cascades inside primary cilia is key to signal propagation. Yet little is known about the dynamics of ciliary membrane proteins besides a possible role for motor-driven Intraflagellar Transport (IFT). To characterize these dynamics, we imaged single molecules of Somatostatin Receptor 3 (SSTR3, a GPCR) and Smoothened (Smo, a Hedgehog signal transducer) in the ciliary membrane. While IFT trains moved processively from one end of the cilium to the other, single SSTR3 and Smo underwent mostly diffusive behavior interspersed with short periods of directional movements. Statistical subtraction of instant velocities revealed that SSTR3 and Smo spent less than a third of their time undergoing active transport. Finally, SSTR3 and IFT movements could be uncoupled by perturbing either membrane protein diffusion or active transport. Thus ciliary membrane proteins move predominantly by diffusion, and attachment to IFT trains is transient and stochastic rather than processive or spatially determined. DOI:http://dx.doi.org/10.7554/eLife.00654.001.
View details for DOI 10.7554/eLife.00654
View details for PubMedID 23930224
View details for PubMedCentralID PMC3736543
- Theoretical study of nanostructured alkaline exchange membrane transport property 2013
- Coarse grain model of nanostructured alkaline exchange membranes: Phase behavior and transport property predictions 2013
- Theoretical study of nanostructured alkaline exchange membrane phase behavior and transport property 2013
- Theoretical model for HP1-Induced heterochromatin formation 2013
- Systematic coarse-graining of the wormlike chain model for dynamic simulations 2013
- Semiflexible polymer model for charge mobility in liquid crystalline organic semiconductors 2013
- Self-assembled protein structures are altered by underlying fluctuations 2013
- Physical modeling of chromosome segregation in E. Coli reveals impact of force and DNA relaxation 2013
- Effect of conformation in charge transport for semiflexible polymers 2013
- An amphiphilic polysulfone-graft-poly(ethylene) glycol random copolymer for alkaline exchange membrane fuel cells 2013
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Discretizing elastic chains for coarse-grained polymer models
SOFT MATTER
2013; 9 (29): 7016-7027
View details for DOI 10.1039/c3sm50311a
View details for Web of Science ID 000321273000046
- Membrane Fluctuations Destrabilize Clathrin Protein Lattice Order Biophysical Journal 2013
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Dynamic remodelling of disordered protein aggregates is an alternative pathway to achieve robust self-assembly of nanostructures
SOFT MATTER
2013; 9 (38): 9137-9145
View details for DOI 10.1039/c3sm50830g
View details for Web of Science ID 000324423700012
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Intrinsic fluctuations lead to broad range of transduced forces in tethered-bead single-molecule experiments
PHYSICAL REVIEW E
2012; 86 (2)
Abstract
We build a theoretical platform for predicting the behavior of tethered-bead single-molecule experiments, accounting for bead translational and rotational fluctuations, the specific type of experimental setup, and the detailed application of tension to the tether molecule. Within this framework, the external force applied to the bead is distinguished from the instantaneous force transduced to the tether molecule, resulting in a distinction between the observable response of the bead and the underlying force fluctuations felt by the tether that directly affect the biomolecular processes being studied. Our theoretical model indicates that the spread of the distribution of tether forces increases with applied external force, resulting in substantial deviations between the external and tether forces. We find that the impact of rotational and translational fluctuations of the bead motion is larger in magnetic tweezers than optical tweezers. However, this distinction diminishes at large external forces, and our asymptotic expressions offer a simple route for experimental analyses. Overall, our theory demonstrates that fluctuations in the tether molecule due to bead rotation and translation lead to a broad range of tether forces.
View details for DOI 10.1103/PhysRevE.86.021902
View details for Web of Science ID 000307278000001
View details for PubMedID 23005780
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Force fluctuations impact kinetics of biomolecular systems
PHYSICAL REVIEW E
2012; 86 (1)
Abstract
A wide array of biological processes occur at rates that vary significantly with force. Instantaneous molecular forces fluctuate due to thermal noise and active processes, leading to concomitant fluctuations in biomolecular rate constants. We demonstrate that such fluctuations have a dramatic effect on the transition kinetics of force-dependent processes. As an illustrative, biologically relevant example, we model the pausing of eukaryotic RNA polymerase as it transcribes nucleosomal DNA. Incorporating force fluctuations in the model yields qualitatively different predictions for the pausing time scales when compared to behavior under the average force alone. We use our model to illustrate the broad range of behaviors that can arise in biomolecular processes that are susceptible to force fluctuations. The fluctuation time scale, which varies significantly for in vivo biomolecular processes, yields very different results for overall rates and dramatically alters the force regime of relevance to the transition. Our results emphasize the importance of transient high-force behavior for determining kinetics in the fluctuating environment of a living cell.
View details for DOI 10.1103/PhysRevE.86.011906
View details for Web of Science ID 000306331400005
View details for PubMedID 23005451
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Analytical Tools To Distinguish the Effects of Localization Error, Confinement, and Medium Elasticity on the Velocity Autocorrelation Function
BIOPHYSICAL JOURNAL
2012; 102 (11): 2443-2450
Abstract
Single particle tracking is a powerful technique for investigating the dynamic behavior of biological molecules. However, many of the analytical tools are prone to generate results that can lead to mistaken interpretations of the underlying transport process. Here, we explore the effects of localization error and confinement on the velocity autocorrelation function, Cυ. We show that calculation of Cυ across a range of discretizations can distinguish the effects of localization error, confinement, and medium elasticity. Thus, under certain regimes, Cυ can be used as a diagnostic tool to identify the underlying mechanism of anomalous diffusion. Finally, we apply our analysis to experimental data sets of chromosomal loci and RNA-protein particles in Escherichia coli.
View details for DOI 10.1016/j.bpj.2012.03.062
View details for Web of Science ID 000305003100006
View details for PubMedID 22713559
View details for PubMedCentralID PMC3368140
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Nonthermal ATP-dependent fluctuations contribute to the in vivo motion of chromosomal loci
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2012; 109 (19): 7338-7343
Abstract
Chromosomal loci jiggle in place between segregation events in prokaryotic cells and during interphase in eukaryotic nuclei. This motion seems random and is often attributed to brownian motion. However, we show here that locus dynamics in live bacteria and yeast are sensitive to metabolic activity. When ATP synthesis is inhibited, the apparent diffusion coefficient decreases, whereas the subdiffusive scaling exponent remains constant. Furthermore, the magnitude of locus motion increases more steeply with temperature in untreated cells than in ATP-depleted cells. This "superthermal" response suggests that untreated cells have an additional source of molecular agitation, beyond thermal motion, that increases sharply with temperature. Such ATP-dependent fluctuations are likely mechanical, because the heat dissipated from metabolic processes is insufficient to account for the difference in locus motion between untreated and ATP-depleted cells. Our data indicate that ATP-dependent enzymatic activity, in addition to thermal fluctuations, contributes to the molecular agitation driving random (sub)diffusive motion in the living cell.
View details for DOI 10.1073/pnas.1119505109
View details for Web of Science ID 000304090600048
View details for PubMedID 22517744
View details for PubMedCentralID PMC3358901
- Force Fluctuations Play a Key Role in Biomolecular Kinetics 2012
- Viral Packaging of Nucleic Acids Polymer Science: A Comprehensive Reference edited by Möller, M., Matyjaszewski, K. Elsevier Academic Press, San Diego, CA.. 2012: 231–245
- Self-Assembly of Clathrin Protein 3D Structures 2012
- Force Fluctuations Impact Genome Processing Kinetics 2012
- Bridging Length Scales: Hierarchical Coarse-Graining of Elastic Biopolymer Models 2012
- Stability of Heterochromatin Condensation Due to Cooperative Binding 2012
- Membrane fluctuations alter the fluidity of clathrin protein lattices 2012
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Selective dispersion of high purity semiconducting single-walled carbon nanotubes with regioregular poly(3-alkylthiophene)s
NATURE COMMUNICATIONS
2011; 2
Abstract
Conjugated polymers, such as polyfluorene and poly(phenylene vinylene), have been used to selectively disperse semiconducting single-walled carbon nanotubes (sc-SWNTs), but these polymers have limited applications in transistors and solar cells. Regioregular poly(3-alkylthiophene)s (rr-P3ATs) are the most widely used materials for organic electronics and have been observed to wrap around SWNTs. However, no sorting of sc-SWNTs has been achieved before. Here we report the application of rr-P3ATs to sort sc-SWNTs. Through rational selection of polymers, solvent and temperature, we achieved highly selective dispersion of sc-SWNTs. Our approach enables direct film preparation after a simple centrifugation step. Using the sorted sc-SWNTs, we fabricate high-performance SWNT network transistors with observed charge-carrier mobility as high as 12 cm(2) V(-1) s(-1) and on/off ratio of >10(6). Our method offers a facile and a scalable route for separating sc-SWNTs and fabrication of electronic devices.
View details for DOI 10.1038/ncomms1545
View details for PubMedID 22086341
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Theoretical and Computational Modeling of Target-Site Search Kinetics In Vitro and In Vivo
BIOPHYSICAL JOURNAL
2011; 101 (4): 856-865
Abstract
Access to genetically encoded data depends on the dynamics of DNA-binding proteins searching for specific target sites in the genome. This search process is thought to occur by facilitated diffusion-a combination of three-dimensional diffusion and one-dimensional sliding. Although facilitated diffusion is capable of significantly speeding up the search in vitro, the importance of this mechanism in vivo remains unclear. We use numeric simulations and analytical theory to model the target-search dynamics of DNA-binding proteins under a wide range of conditions. Our models reproduce experimental measurements of search-rate enhancement within bulk in vitro experiments, as well as the target search time for transcription factors measured in vivo. We find that facilitated diffusion can accelerate the search process only for a limited range of parameters and only under dilute DNA conditions. We address the role of DNA configuration and confinement, demonstrating that facilitated diffusion does not speed up the search on coiled versus straight DNA. Furthermore, we show that, under in vivo conditions, the search process becomes effectively diffusive and is independent of DNA configuration. We believe our results cast in a new light the role of facilitated diffusion in DNA targeting kinetics within the cell.
View details for DOI 10.1016/j.bpj.2011.06.066
View details for Web of Science ID 000294103600015
View details for PubMedID 21843476
View details for PubMedCentralID PMC3175062
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A Boltzmann-weighted hopping model of charge transport in organic semicrystalline films
JOURNAL OF APPLIED PHYSICS
2011; 109 (11)
View details for DOI 10.1063/1.3594686
View details for Web of Science ID 000292214700082
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Tension-dependent structural deformation alters single-molecule transition kinetics
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2011; 108 (5): 1885-1890
Abstract
We analyze the response of a single nucleosome to tension, which serves as a prototypical biophysical measurement where tension-dependent deformation alters transition kinetics. We develop a statistical-mechanics model of a nucleosome as a wormlike chain bound to a spool, incorporating fluctuations in the number of bases bound, the spool orientation, and the conformations of the unbound polymer segments. With the resulting free-energy surface, we perform dynamic simulations that permit a direct comparison with experiments. This simple approach demonstrates that the experimentally observed structural states at nonzero tension are a consequence of the tension and that these tension-induced states cease to exist at zero tension. The transitions between states exhibit substantial deformation of the unbound polymer segments. The associated deformation energy increases with tension; thus, the application of tension alters the kinetics due to tension-induced deformation of the transition states. This mechanism would arise in any system where the tether molecule is deformed in the transition state under the influence of tension.
View details for DOI 10.1073/pnas.1010047108
View details for Web of Science ID 000286804700028
View details for PubMedID 21245354
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Impact of defect creation and motion on the thermodynamics and large-scale reorganization of self-assembled clathrin lattices
SOFT MATTER
2011; 7 (19): 8789-8799
View details for DOI 10.1039/c1sm05053b
View details for Web of Science ID 000295085700015
- Impact of Defect Creation and Motion On the Large-Scale Reorganization Dynamics of Self-Assembled Clathrin Lattices 2011
- Force Fluctuations Dictate Kinetics of Biomolecular Systems 2011
- Theoretical Modeling of the Packaging and Accessibility of DNA 2011
- Heterochromatin Protein 1: An Epigenetic Mechanism for Chromatin Condensation 2011
- Force Fluctuations Dictate Kinetics of Biomolecular Systems 2011
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Local Geometry and Elasticity in Compact Chromatin Structure
BIOPHYSICAL JOURNAL
2010; 99 (12): 3941-3950
Abstract
The hierarchical packaging of DNA into chromatin within a eukaryotic nucleus plays a pivotal role in both the accessibility of genomic information and the dynamics of replication. Our work addresses the role of nanoscale physical and geometric properties in determining the structure of chromatin at the mesoscale level. We study the packaging of DNA in chromatin fibers by optimization of regular helical morphologies, considering the elasticity of the linker DNA as well as steric packing of the nucleosomes and linkers. Our model predicts a broad range of preferred helix structures for a fixed linker length of DNA; changing the linker length alters the predicted ensemble. Specifically, we find that the twist registry of the nucleosomes, as set by the internucleosome repeat length, determines the preferred angle between the nucleosomes and the fiber axis. For moderate to long linker lengths, we find a number of energetically comparable configurations with different nucleosome-nucleosome interaction patterns, indicating a potential role for kinetic trapping in chromatin fiber formation. Our results highlight the key role played by DNA elasticity and local geometry in regulating the hierarchical packaging of the genome.
View details for DOI 10.1016/j.bpj.2010.10.024
View details for Web of Science ID 000285438900017
View details for PubMedID 21156136
View details for PubMedCentralID PMC3000514
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Subdiffusive motion of a polymer composed of subdiffusive monomers
PHYSICAL REVIEW E
2010; 82 (1)
Abstract
We use Brownian dynamics simulations and analytical theory to investigate the physical principles underlying subdiffusive motion of a polymer. Specifically, we examine the consequences of confinement, self-interaction, viscoelasticity, and random waiting on monomer motion, as these physical phenomena may be relevant to the behavior of biological macromolecules in vivo. We find that neither confinement nor self-interaction alter the fundamental Rouse mode relaxations of a polymer. However, viscoelasticity, modeled by fractional Langevin motion, and random waiting, modeled with a continuous time random walk, lead to significant and distinct deviations from the classic polymer-dynamics model. Our results provide diagnostic tools--the monomer mean square displacement scaling and the velocity autocorrelation function--that can be applied to experimental data to determine the underlying mechanism for subdiffusive motion of a polymer.
View details for DOI 10.1103/PhysRevE.82.011913
View details for Web of Science ID 000280067800007
View details for PubMedID 20866654
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Dynamic Strategies for Target-Site Search by DNA-Binding Proteins
BIOPHYSICAL JOURNAL
2010; 98 (12): 2943-2953
Abstract
Gene regulatory proteins find their target sites on DNA remarkably quickly; the experimental binding rate for lac repressor is orders-of-magnitude higher than predicted by free diffusion alone. It has been proposed that nonspecific binding aids the search by allowing proteins to slide and hop along DNA. We develop a reaction-diffusion theory of protein translocation that accounts for transport both on and off the strand and incorporates the physical conformation of DNA. For linear DNA modeled as a wormlike chain, the distribution of hops available to a protein exhibits long, power-law tails that make the long-time displacement along the strand superdiffusive. Our analysis predicts effective superdiffusion coefficients for given nonspecific binding and unbinding rate parameters. Translocation rate exhibits a maximum at intermediate values of the binding rate constant, while search efficiency is optimized at larger binding rate constant values. Thus, our theory predicts a region of values of the nonspecific binding and unbinding rate parameters that balance the protein translocation rate and the efficiency of the search. Published data for several proteins falls within this predicted region of parameter values.
View details for DOI 10.1016/j.bpj.2010.02.055
View details for Web of Science ID 000278913500023
View details for PubMedID 20550907
View details for PubMedCentralID PMC2884260
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Bacterial Chromosomal Loci Move Subdiffusively through a Viscoelastic Cytoplasm
PHYSICAL REVIEW LETTERS
2010; 104 (23)
Abstract
Tracking of fluorescently labeled chromosomal loci in live bacterial cells reveals a robust scaling of the mean square displacement (MSD) as τ(0.39). We propose that the observed motion arises from relaxation of the Rouse modes of the DNA polymer within the viscoelastic environment of the cytoplasm. The time-averaged and ensemble-averaged MSD of chromosomal loci exhibit ergodicity, and the velocity autocorrelation function is negative at short time lags. These observations are most consistent with fractional Langevin motion and rule out a continuous time random walk model as an explanation for anomalous motion in vivo.
View details for DOI 10.1103/PhysRevLett.104.238102
View details for Web of Science ID 000278493500016
View details for PubMedID 20867274
- Modeling Targeted Binding of Nanoparticles to Cell Surfaces 2010
- Theoretical Modeling of the Weaving of Clathrin Into Nanoscale Baskets 2010
- Theoretical Model of HP1-Induced Heterochromatin Formation 2010
- Target site search strategy of DNA-binding proteins 2010
- Role of DNA fluctuations and conformations in RNP polymerase translocation and bulge formation in a single nucleosome 2010
- Role of DNA Elasticity and Nucleosome Geometry in Hierarchical Packaging of Chromatin 2010
- A Predictive Theoretical Model For Clathrin Self-Assembly 2010
- Chromosomal loci move subdiffusively through a viscoelastic cytoplasm Physical Review Letters 2010; 104: 238102
- Translocation Dynamics of DNA-Binding Proteins 2010
- Modeling Effects of Nanoparticle Size and Ligand Display On Targeted Cell-Surface Binding 2010
- Chromosomal Loci Move Subdiffusively through a Viscoelastic Cytoplasm 2010
- The Impact of Biological Fluctuations On Transport Processes within Live Bacterial Cells 2010
- Mathematical Modeling of Charge Transport in Conjugated-Polymer Materials 2010
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Twist- and Tension-Mediated Elastic Coupling between DNA-Binding Proteins
PHYSICAL REVIEW LETTERS
2009; 102 (17)
Abstract
We study the effective interaction between DNA-binding proteins that arises from elastic stresses in the DNA when tension is applied. Using the wormlike chain model, we calculate the free energy cost of introducing multiple nearby bends in the DNA. We find that the bend deformation energy promotes aggregation to straighten the linker DNA, while twist resistance of the linker leads to damped oscillations in the coupling free energy between two proteins. We calculate the mean first encounter time for proteins sliding along DNA, indicating, in some cases, an optimal applied tension for protein assembly. Our results highlight the need to consider DNA twist even when no torsion is applied and the DNA ends are free to rotate. The variable-range oscillatory coupling between DNA-binding proteins may provide a versatile mechanism for tension-mediated gene regulation.
View details for DOI 10.1103/PhysRevLett.102.178102
View details for Web of Science ID 000265948300074
View details for PubMedID 19518837
- Twist and Tension-Mediated Elastic Coupling between DNA-Bending Proteins 2009
- Target Site Search Strategy Of Gene Regulatory Proteins 2009
- Theoretical model for the self-assembly of clathrin into targeted nanoscale assemblies 2009
- Target site search strategy of gene regulatory proteins 2009
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End-to-end distribution for a wormlike chain in arbitrary dimensions
PHYSICAL REVIEW E
2008; 77 (6)
Abstract
We construct an efficient methodology for calculating wormlike chain statistics in arbitrary D dimensions over all chain rigidities, from fully rigid to completely flexible. The structure of our exact analytical solution for the end-to-end distribution function for a wormlike chain in arbitrary D dimensions in Fourier-Laplace space (i.e., Fourier-transformed end position and Laplace-transformed chain length) adopts the form of an infinite continued fraction, which is advantageous for its compact structure and stability for numerical implementation. We then proceed to present a step-by-step methodology for performing the Fourier-Laplace inversion in order to make full use of our results in general applications. Asymptotic methods for evaluating the Laplace inversion (power-law expansion and Rayleigh-Schrödinger perturbation theory) are employed in order to improve the accuracy of the numerical inversions of the end-to-end distribution function in real space. We adapt our results to the evaluation of the single-chain structure factor, rendering simple, closed-form expressions that facilitate comparison with scattering experiments. Using our techniques, the accuracy of the end-to-end distribution function is enhanced up to the limit of the machine precision. We demonstrate the utility of our methodology with realizations of the chain statistics, giving a general methodology that can be applied to a wide range of biophysical problems.
View details for DOI 10.1103/PhysRevE.77.061803
View details for Web of Science ID 000257287500091
View details for PubMedID 18643291
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Optical measurement of mechanical forces inside short DNA loops
BIOPHYSICAL JOURNAL
2008; 94 (6): 2179-2186
Abstract
Knowledge of the mechanical properties of double-stranded DNA (dsDNA) is essential to understand the role of dsDNA looping in gene regulation and the mechanochemistry of molecular machines that operate on dsDNA. Here, we use a newly developed tool, force sensors with optical readout, to measure the forces inside short, strained loops composed of both dsDNA and single-stranded DNA. By varying the length of the loops and their proportion of dsDNA, it was possible to vary their internal forces from 1 pN to >20 pN. Surprisingly, internal loop forces changed erratically as the amount of dsDNA was increased for a given loop length, with the effect most notable in the smallest loop (57 nucleotides). Monte Carlo simulations based on the helical wormlike chain model accurately predict internal forces when more than half of the loop is dsDNA but fail otherwise. Mismatches engineered into the double-stranded regions increased flexibility, suggesting that Watson-Crick basepaired dsDNA can withstand high compressive forces without recourse to multibase melts. Fluorescence correlation spectroscopy further excluded transient melting (microsecond to millisecond duration) as a mechanism for relief of compressive forces in the tested dsDNAs. DNA loops with integrated force sensors may allow the comprehensive mapping of the elasticity of short dsDNAs as a function of both sequence and salt.
View details for DOI 10.1529/biophysj.107.114413
View details for Web of Science ID 000253676200022
View details for PubMedID 18065484
View details for PubMedCentralID PMC2257878
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Three-dimensional architecture of the bacteriophage phi 29 packaged genome and elucidation of its packaging process
VIROLOGY
2008; 371 (2): 267-277
Abstract
The goal of the work reported here is to understand the precise molecular mechanism of the process of DNA packaging in dsDNA bacteriophages. Cryo-EM was used to directly visualize the architecture of the DNA inside the capsid and thus to measure fundamental physical parameters such as inter-strand distances, local curvatures, and the degree of order. We obtained cryo-EM images of bacteriophage that had packaged defined fragments of the genome as well as particles that had partially completed the packaging process. The resulting comparison of structures observed at intermediate and final stages shows that there is no unique, deterministic DNA packaging pathway. Monte Carlo simulations of the packaging process provide insights on the forces involved and the resultant structures.
View details for DOI 10.1016/j.virol.2007.07.035
View details for Web of Science ID 000253060200007
View details for PubMedID 18001811
- Unraveling the Dynamics of Supercoiled DNA with Theoretical Modeling 2008
- Structural Fluctuations In the Nucleosome Core Particle 2008
- Chemical Physics Of DNA Packaging In A Nucleosome Core Particle 2008
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Direct optical measurement of stresses inside circularized DNA loops
51st Annual Meeting of the Biophysical-Society
CELL PRESS. 2007: 350A–350A
View details for Web of Science ID 000243972402187
- Target-Site Search Strategies of DNA-Binding Proteins 2007
- Theory of Translational and Rotational Fluctuations in Tethered-Bead Single-Molecule Experiments 2007
- Target Site Search Strategy Of Gene Regulatory Proteins 2007
- Chemical Physics Of DNA Packaging In A Nucleosome Core Particle 2007
- Wrapping Transitions for a Single Nucleosome Under Tension 2007
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High flexibility of DNA on short length scales probed by atomic force microscopy
NATURE NANOTECHNOLOGY
2006; 1 (2): 137-141
Abstract
The mechanics of DNA bending on intermediate length scales (5-100 nm) plays a key role in many cellular processes, and is also important in the fabrication of artificial DNA structures, but previous experimental studies of DNA mechanics have focused on longer length scales than these. We use high-resolution atomic force microscopy on individual DNA molecules to obtain a direct measurement of the bending energy function appropriate for scales down to 5 nm. Our measurements imply that the elastic energy of highly bent DNA conformations is lower than predicted by classical elasticity models such as the worm-like chain (WLC) model. For example, we found that on short length scales, spontaneous large-angle bends are many times more prevalent than predicted by the WLC model. We test our data and model with an interlocking set of consistency checks. Our analysis also shows how our model is compatible with previous experiments, which have sometimes been viewed as confirming the WLC.
View details for DOI 10.1038/nnano.2006.63
View details for Web of Science ID 000243902600017
View details for PubMedID 18654166
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Effect of force on mononucleosomal dynamics
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2006; 103 (43): 15871-15876
Abstract
Using single-molecule optical-trapping techniques, we examined the force-induced dynamic behavior of a single nucleosome core particle. Our experiments using the DNA construct containing the 601 nucleosome-positioning sequence revealed that the nucleosome unravels in at least two major stages. The first stage, which we attributed to the unraveling of the first DNA wrap around the histone octamer, could be mechanically induced in a reversible manner, and when kept at constant force within a critical force range, exhibited two-state hopping behavior. From the hopping data, we determined the force-dependent equilibrium constant and rates for opening/closing of the outer wrap. Our investigation of the second unraveling event at various loading rates, which we attributed to the inner DNA wrap, revealed that this unraveling event cannot be described as a simple two-state process. We also looked at the behavior of the mononucleosome in a high-salt buffer, which revealed that the outer DNA wrap is more sensitive to changes in the ionic environment than the inner DNA wrap. These findings are needed to understand the energetics of nucleosome remodeling.
View details for DOI 10.1073/pnas.0607526103
View details for Web of Science ID 000241568500027
View details for PubMedID 17043216
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Wormlike chain statistics with twist and fixed ends
EUROPHYSICS LETTERS
2006; 73 (5): 684-690
View details for DOI 10.1209/epl/i2005-10447-9
View details for Web of Science ID 000235778000005
- DNA Structure within a Virus Particle 2006
- Coupled Translational and Rotational Fluctuations of Tethered Beads 2006
- Wrapping Transitions in a Single Nucleosome Under Tension 2006
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Biocompatible force sensor with optical readout and dimensions of 6 nm(3)
NANO LETTERS
2005; 5 (7): 1509-1514
Abstract
We have developed a nanoscopic force sensor with optical readout. The sensor consists of a single-stranded DNA oligomer flanked by two dyes. The DNA acts as a nonlinear spring: when the spring is stretched, the distance between the two dyes increases, resulting in reduced Förster resonance energy transfer. The sensor was calibrated between 0 and 20 pN using a combined magnetic tweezers/single-molecule fluorescence microscope. We show that it is possible to tune the sensor's force response by varying the interdye spacing and that the FRET efficiency of the sensors decreases with increasing force. We demonstrate the usefulness of these sensors by using them to measure the forces internal to a single polymer molecule, a small DNA loop. Partial conversion of the single-stranded DNA loop to a double-stranded form results in the accumulation of strain: a force of approximately 6 pN was measured in the loop upon hybridization. The sensors should allow measurement of forces internal to various materials, including programmable DNA self-assemblies, polymer meshes, and DNA-based machines.
View details for DOI 10.1021/nl050875h
View details for Web of Science ID 000230571300058
View details for PubMedID 16178266
- DNA packaging in bacteriophage: Is twist important? Biophysical Journal 2005; 88: 3912
- Semiflexible chain statistics with fixed end orientations 2005
- Topological considerations in nucleic acid hybridization kinetics Nucleic Acids Research 2005; 33 (13): 4090
- End-to-end distance vector distribution with fixed end orientations for the wormlike chain model Phys. Rev. E 2005; 72: 41802
- Exact results for a semiflexible polymer chain in an aligning field Macromolecules 2004; 37: 5814
- Semiflexible polymer solutions: I. phase behavior and single-chain statistics Journal of Chemical Physics 2003; 119: 13113
- A semiflexible polymer confined to a spherical surface Physical Review Letters 2003; 91: 166102
- Towards an Understanding of the Physical Manipulation of DNA 2003
- Twist Effect in DNA Packaging 2003
- Shape dynamics of elastic filaments due to internal strain 2002
- Free expansion of elastic filaments Physical Review E 2001; 64: 61802