Honors & Awards
EMBO Long-Term Fellowship, European Molecular Biology Organization (2019)
Participation in the Lindau Nobel Laureates Meeting, Council for the Lindau Nobel Laureate Meetings (2019)
Doctor of Philosophy, Max Planck Institute of Biophysics and Goethe University Frankfurt, Physics (2019)
Master of Science, University of Stuttgart, Physics (2014)
Bachelor of Science, University of Konstanz, Physics (2011)
Membrane perforation by the pore-forming toxin pneumolysin
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2019; 116 (27): 13352–57
Pneumolysin (PLY), a major virulence factor of Streptococcus pneumoniae, perforates cholesterol-rich lipid membranes. PLY protomers oligomerize as rings on the membrane and then undergo a structural transition that triggers the formation of membrane pores. Structures of PLY rings in prepore and pore conformations define the beginning and end of this transition, but the detailed mechanism of pore formation remains unclear. With atomistic and coarse-grained molecular dynamics simulations, we resolve key steps during PLY pore formation. Our simulations confirm critical PLY membrane-binding sites identified previously by mutagenesis. The transmembrane β-hairpins of the PLY pore conformation are stable only for oligomers, forming a curtain-like membrane-spanning β-sheet. Its hydrophilic inner face draws water into the protein-lipid interface, forcing lipids to recede. For PLY rings, this zone of lipid clearance expands into a cylindrical membrane pore. The lipid plug caught inside the PLY ring can escape by lipid efflux via the lower leaflet. If this path is too slow or blocked, the pore opens by membrane buckling, driven by the line tension acting on the detached rim of the lipid plug. Interestingly, PLY rings are just wide enough for the plug to buckle spontaneously in mammalian membranes. In a survey of electron cryo-microscopy (cryo-EM) and atomic force microscopy images, we identify key intermediates along both the efflux and buckling pathways to pore formation, as seen in the simulations.
View details for DOI 10.1073/pnas.1904304116
View details for Web of Science ID 000473427900036
View details for PubMedID 31209022
View details for PubMedCentralID PMC6613103
Hydrodynamics of Diffusion in Lipid Membrane Simulations
PHYSICAL REVIEW LETTERS
2018; 120 (26): 268104
By performing molecular dynamics simulations with up to 132 million coarse-grained particles in half-micron sized boxes, we show that hydrodynamics quantitatively explains the finite-size effects on diffusion of lipids, proteins, and carbon nanotubes in membranes. The resulting Oseen correction allows us to extract infinite-system diffusion coefficients and membrane surface viscosities from membrane simulations despite the logarithmic divergence of apparent diffusivities with increasing box width. The hydrodynamic theory of diffusion applies also to membranes with asymmetric leaflets and embedded proteins, and to a complex plasma-membrane mimetic.
View details for DOI 10.1103/PhysRevLett.120.268104
View details for Web of Science ID 000436940400030
View details for PubMedID 30004782
Coarse-grained simulations of polyelectrolyte complexes: MARTINI models for poly(styrene sulfonate) and poly(diallyldimethylammonium)
JOURNAL OF CHEMICAL PHYSICS
2015; 143 (24): 243151
We present simulations of aqueous polyelectrolyte complexes with new MARTINI models for the charged polymers poly(styrene sulfonate) and poly(diallyldimethylammonium). Our coarse-grained polyelectrolyte models allow us to study large length and long time scales with regard to chemical details and thermodynamic properties. The results are compared to the outcomes of previous atomistic molecular dynamics simulations and verify that electrostatic properties are reproduced by our MARTINI coarse-grained approach with reasonable accuracy. Structural similarity between the atomistic and the coarse-grained results is indicated by a comparison between the pair radial distribution functions and the cumulative number of surrounding particles. Our coarse-grained models are able to quantitatively reproduce previous findings like the correct charge compensation mechanism and a reduced dielectric constant of water. These results can be interpreted as the underlying reason for the stability of polyelectrolyte multilayers and complexes and validate the robustness of the proposed models.
View details for DOI 10.1063/1.4937805
View details for Web of Science ID 000370412900057
View details for PubMedID 26723636
PDADMAC/PSS Oligoelectrolyte Multilayers: Internal Structure and Hydration Properties at Early Growth Stages from Atomistic Simulations.
Molecules (Basel, Switzerland)
2020; 25 (8)
We analyze the internal structure and hydration properties of poly(diallyl dimethyl ammonium chloride)/poly(styrene sulfonate sodium salt) oligoelectrolyte multilayers at early stages of their layer-by-layer growth process. Our study is based on large-scale molecular dynamics simulations with atomistic resolution that we presented recently [Sanchez et al., Soft Matter 2019, 15, 9437], in which we produced the first four deposition cycles of a multilayer obtained by alternate exposure of a flat silica substrate to aqueous electrolyte solutions of such polymers at 0.1M of NaCl. In contrast to any previous work, here we perform a local structural analysis that allows us to determine the dependence of the multilayer properties on the distance to the substrate. We prove that the large accumulation of water and ions next to the substrate observed in previous overall measurements actually decreases the degree of intrinsic charge compensation, but this remains as the main mechanism within the interface region. We show that the range of influence of the substrate reaches approximately 3 nm, whereas the structure of the outer region is rather independent from the position. This detailed characterization is essential for the development of accurate mesoscale models able to reach length and time scales of technological interest.
View details for DOI 10.3390/molecules25081848
View details for PubMedID 32316422
- REPLY TO DESIKAN ET AL.: Micelle formation among variousmechanisms of toxin pore formation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2020; 117 (10): 5109–10
Atomistic simulation of PDADMAC/PSS oligoelectrolyte multilayers: overall comparison of tri- and tetra-layer systems.
By employing large-scale molecular dynamics simulations of atomistically resolved oligoelectrolytes in aqueous solutions, we study in detail the first four layer-by-layer deposition cycles of an oligoelectrolyte multilayer made of poly(diallyl dimethyl ammonium chloride)/poly(styrene sulfonate sodium salt) (PDADMAC/PSS). The multilayers are grown on a silica substrate in 0.1 M NaCl electrolyte solutions and the swollen structures are then subsequently exposed to varying added salt concentration. We investigated the microscopic properties of the films, analyzing in detail the differences between three- and four-layer systems. Our simulations provide insights into the early stages of growth of a multilayer, which are particularly challenging for experimental observations. We found rather strong complexation of the oligoelectrolytes, with fuzzy layering of the film structure. The main charge compensation mechanism is for all cases intrinsic, whereas extrinsic compensation is relatively enhanced for the layer of the last deposition cycle. In addition, we quantified other fundamental observables of these systems, such as the film thickness, water uptake, and overcharge fractions for each deposition layer.
View details for DOI 10.1039/c9sm02010a
View details for PubMedID 31720676
- Perceptions of publication pressure in the Max Planck Society. Nature human behaviour 2019; 3 (10): 1029–30
Finite-Size-Corrected Rotational Diffusion Coefficients of Membrane Proteins and Carbon Nanotubes from Molecular Dynamics Simulations
JOURNAL OF PHYSICAL CHEMISTRY B
2019; 123 (24): 5099–5106
We investigate system-size effects on the rotational diffusion of membrane proteins and other membrane-embedded molecules in molecular dynamics simulations. We find that the rotational diffusion coefficient slows down relative to the infinite-system value by a factor of one minus the ratio of protein and box areas. This correction factor follows from the hydrodynamics of rotational flows under periodic boundary conditions and is rationalized in terms of Taylor-Couette flow. For membrane proteins like transporters, channels, or receptors in typical simulation setups, the protein-covered area tends to be relatively large, requiring a significant finite-size correction. Molecular dynamics simulations of the protein adenine nucleotide translocase (ANT1) and of a carbon nanotube porin in lipid membranes show that the hydrodynamic finite-size correction for rotational diffusion is accurate in standard-use cases. The dependence of the rotational diffusion on box size can be used to determine the membrane viscosity.
View details for DOI 10.1021/acs.jpcb.9b01656
View details for Web of Science ID 000472800700009
View details for PubMedID 31132280
View details for PubMedCentralID PMC6750896
Molecular dynamics simulations of carbon nanotube porins in lipid bilayers
2018; 209: 341–58
Artificial channels made of carbon nanotube (CNT) porins are promising candidates for applications in filtration and molecular delivery devices. Their symmetric shape and high mechanical, chemical, and thermal stability ensure well-defined transport properties, and at the same time make them ideal model systems for more complicated membrane protein pores. As the technology to produce and tune CNTs advances, simulations can aid in the design of customized membrane porins. Here we concentrate on CNTs embedded in lipid membranes. To derive design guidelines, we systematically studied the interaction of CNT porins with their surrounding lipids. For our simulations, we developed an AMBER- and Lipid14-compatible parameterization scheme for CNTs with different chirality and with functional groups attached to their rim, and a flexible coarse-grained description for open-ended CNTs fitting to the MARTINI lipid model. We found that the interaction with lipid acyl chains is independent of the CNT chirality and the chemical details of functional groups at the CNT rims. The latter, however, are important for the interactions with lipid head groups, and for water permeability. The orientation and permeability of the pore are mainly determined by how well its hydrophobicity pattern matches the membrane. By identifying the factors that determine the structure both of isolated CNTs in lipid membranes and of CNT clusters, we set the foundation for a targeted design of CNT-membrane systems.
View details for DOI 10.1039/c8fd00011e
View details for Web of Science ID 000448410600022
View details for PubMedID 29974904
- Biomimetic water channels: general discussion FARADAY DISCUSSIONS 2018; 209: 205–29
- The modelling and enhancement of water hydrodynamics: general discussion FARADAY DISCUSSIONS 2018; 209: 273–85
Carbon Nanotubes Mediate Fusion of Lipid Vesicles
2017; 11 (2): 1273–80
The fusion of lipid membranes is opposed by high energetic barriers. In living organisms, complex protein machineries carry out this biologically essential process. Here we show that membrane-spanning carbon nanotubes (CNTs) can trigger spontaneous fusion of small lipid vesicles. In coarse-grained molecular dynamics simulations, we find that a CNT bridging between two vesicles locally perturbs their lipid structure. Their outer leaflets merge as the CNT pulls lipids out of the membranes, creating an hourglass-shaped fusion intermediate with still intact inner leaflets. As the CNT moves away from the symmetry axis connecting the vesicle centers, the inner leaflets merge, forming a pore that completes fusion. The distinct mechanism of CNT-mediated membrane fusion may be transferable, providing guidance in the development of fusion agents, e.g., for the targeted delivery of drugs or nucleic acids.
View details for DOI 10.1021/acsnano.6b05434
View details for Web of Science ID 000395357300018
View details for PubMedID 28103440
Divergent Diffusion Coefficients in Simulations of Fluids and Lipid Membranes
JOURNAL OF PHYSICAL CHEMISTRY B
2016; 120 (33): 8722–32
We investigate the dependence of single-particle diffusion coefficients on the size and shape of the simulation box in molecular dynamics simulations of fluids and lipid membranes. We find that the diffusion coefficients of lipids and a carbon nanotube embedded in a lipid membrane diverge with the logarithm of the box width. For a neat Lennard-Jones fluid in flat rectangular boxes, diffusion becomes anisotropic, diverging logarithmically in all three directions with increasing box width. In elongated boxes, the diffusion coefficients normal to the long axis diverge linearly with the height-to-width ratio. For both lipid membranes and neat fluids, this behavior is predicted quantitatively by hydrodynamic theory. Mean-square displacements in the neat fluid exhibit intermediate regimes of anomalous diffusion, with t ln t and t(3/2) components in flat and elongated boxes, respectively. For membranes, the large finite-size effects, and the apparent inability to determine a well-defined lipid diffusion coefficient from simulation, rationalize difficulties in comparing simulation results to each other and to those from experiments.
View details for DOI 10.1021/acs.jpcb.6b05102
View details for Web of Science ID 000382180200061
View details for PubMedID 27385207
- Properties of the polarizable MARTINI water model: A comparative study for aqueous electrolyte solutions JOURNAL OF MOLECULAR LIQUIDS 2015; 212: 103–10