Honors & Awards

  • Robert Wade Brown Award, University of North Texas (2018)
  • Chemical Computing Group Excellence Award, 255th ACS National Meeting (New Orleans, LA), CCG/ACS (2018)
  • ASMS Sanibel Conference Travel Award, ASMS (2018)
  • Award for Best Poster, 6th EU-US Conference on Repair of Endogenous DNA Damage, University of Udine (2017)
  • COS Travel Grant, University of North Texas (2017)
  • Ed and Julie Hodges Memorial Scholarship, University of North Texas (2017)
  • ANTON MD Simulations Computing Award (PSCA15038), Pittsburgh Supercomputing Center (2015)
  • Chemistry-Biology Interface (CBI) Fellowship, Chemistry Division, Wayne State University (2015-2016)
  • Honor Citation for Teaching Services in Chemistry, Wayne State University (2013)

Professional Education

  • Doctor of Philosophy, University of North Texas (2018)
  • Bachelor of Science, University of Michigan Dearborn (2011)

All Publications

  • Proton Transfer Dynamics in the Aprotic Proton Accepting Solvent 1-Methylimidazole. The journal of physical chemistry. B Thomaz, J. E., Walker, A. R., Van Wyck, S. J., Meisner, J., Martinez, T. J., Fayer, M. D. 2020


    The dynamics of proton transfer to the aprotic solvent 1-methylimidazole (MeIm, proton acceptor) from the photoacid 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt (HPTS) was investigated using fast fluorescence measurements. The closely related molecule, 8-methoxypyrene-1,3,6-trisulfonic acid trisodium salt (MPTS), which is not a photoacid, was also studied for comparison. Following optical excitation, the wavelength-dependent population dynamics of HPTS in MeIm resulting from the deprotonation process were collected over the entire fluorescence emission window. Analysis of the time-dependent fluorescence spectra revealed four distinct fluorescence bands that appear and decay on different time scales. We label these four states as protonated (P), associated I (AI), associated II (AII), and deprotonated (D). We find that the simple kinetic scheme of P AI AII D is not consistent with the data. Instead, the kinetic scheme that describes the data has P decaying into AI, which mainly goes on to deprotonation (D), but AI can also feed into AII. AII can return to AI or decay to the ground state, but does not deprotonate within experimental error. Quantum chemistry and excited state QM/MM Born-Oppenheimer molecular dynamics simulations indicate that AI and AII are two H-bonding conformations of MeIm to the HPTS hydroxyl, axial, and equatorial, respectively.

    View details for DOI 10.1021/acs.jpcb.0c05525

    View details for PubMedID 32790382

  • Mechanistic insights into photodecarboxylation of fatty acids from classical and QM/MM simulations Walker, A., Lane, T., van den Bedem, H., Martinez, T. AMER CHEMICAL SOC. 2019
  • Unfolding Pathways of Hen Egg-White Lysozyme in Ethanol JOURNAL OF PHYSICAL CHEMISTRY B Walker, A. R., Baddam, N., Cisneros, G. 2019; 123 (15): 3267–71
  • Unfolding Pathways of Hen Egg-White Lysozyme in Ethanol. The journal of physical chemistry. B Walker, A. R., Baddam, N., Cisneros, G. A. 2019


    The aggregation of amyloid fibrils can lead to various diseases including Alzheimer's, Parkinson's disease, and transmissible spongiform encephalopathy. Amyloid fibrils can develop from a variety of proteins in the body as they misfold into a primarily beta-sheet structure and aggregate. Human lysozyme has been shown to have far reaching effects in the human health-a homologous enzyme, hen egg-white lysozyme, has been shown to denature to a primarily beta-sheet structure at low pH and high alcohol content solution. We have studied these systems in atomic-level detail with a combination of constant pH and microsecond long molecular dynamics simulation in explicit solvent, which cumulatively total over 10 mus of simulation time. These studies have allowed us to determine two potential unfolding pathways depending on the protonation state of a key glutamic acid residue as well as the effect of solution dynamics and pH on the unfolding process.

    View details for PubMedID 30912946

  • Computational investigation of single nucleotide polymorphisms in human DNA polymerase kappa Leddin, E., Walker, A., Antczak, N., Stern, H., Palad, C., Coulther, T., Swett, R., Beuning, P., Cisneros, G. AMER CHEMICAL SOC. 2019
  • Reduced structural flexibility for an exonuclease deficient DNA polymerase III mutant. Physical chemistry chemical physics : PCCP Gahlon, H. L., Walker, A. R., Cisneros, G. A., Lamers, M. H., Rueda, D. S. 2018


    DNA synthesis, carried out by DNA polymerases, requires balancing speed and accuracy for faithful replication of the genome. High fidelity DNA polymerases contain a 3'-5' exonuclease domain that can remove misincorporated nucleotides on the 3' end of the primer strand, a process called proofreading. The E. coli replicative polymerase, DNA polymerase III, has spatially separated (55 A apart) polymerase and exonuclease subunits. Here, we report on the dynamics of E. coli DNA polymerase III proofreading in the presence of its processivity factor, the beta2-sliding clamp, at varying base pair termini using single-molecule FRET. We find that the binding kinetics do not depend on the base identity at the termini, indicating a tolerance for DNA mismatches. Further, our single-molecule data and MD simulations show two previously unobserved features: (1) DNA Polymerase III is a highly dynamic protein that adopts multiple conformational states while bound to DNA with matched or mismatched ends, and (2) an exonuclease-deficient DNA polymerase III has reduced conformational flexibility. Overall, our single-molecule experiments provide high time-resolution insight into a mechanism that ensures high fidelity DNA replication to maintain genome integrity.

    View details for DOI 10.1039/c8cp04112a

    View details for PubMedID 30345999

  • Effects of a single point mutation and mismatched base on DNA polymerase III holoenzyme proofreading Walker, A., Gahlon, H., Rueda, D., Cisneros, G. AMER CHEMICAL SOC. 2018
  • Unfolding pathways of hen egg white lysozyme in ethanol; insights from IMS-MS and molecular dynamics Walker, A., Woodall, D., Inutan, E., Baddam, N., Stemmer, P., Trimpin, S., Cisneros, G. AMER CHEMICAL SOC. 2018
  • Characterization of Nine Cancer-Associated Variants in Human DNA Polymerase κ. Chemical research in toxicology Antczak, N. M., Walker, A. R., Stern, H. R., Leddin, E. M., Palad, C., Coulther, T. A., Swett, R. J., Cisneros, G. A., Beuning, P. J. 2018


    Specialized DNA damage-bypass Y-family DNA polymerases contribute to cancer prevention by providing cellular tolerance to DNA damage that can lead to mutations and contribute to cancer progression by increasing genomic instability. Y-family polymerases can also bypass DNA adducts caused by chemotherapy agents. One of the four human Y-family DNA polymerases, DNA polymerase (pol) κ, has been shown to be specific for bypass of minor groove adducts and inhibited by major groove adducts. In addition, mutations in the gene encoding pol κ are associated with different types of cancers as well as with chemotherapy responses. We characterized nine variants of pol κ whose identity was inferred from cancer-associated single nucleotide polymorphisms for polymerization activity on undamaged and damaged DNA, their abilities to extend from mismatched or damaged base pairs at primer termini, and overall stability and dynamics. We find that these pol κ variants generally fall into three categories: similar activity to wild-type (WT) pol κ (L21F, I39T, P169T, F192C, and E292K), more active than WT pol κ (S423R), and less active than pol κ (R219I, R298H, and Y432S). Of these, only pol κ variants R298H and Y432S had markedly reduced thermal stability. Molecular dynamics (MD) simulations with undamaged DNA revealed that the active variant F192C and more active variant S423R with either correct or incorrect incoming nucleotide mimic WT pol κ with the correct incoming nucleotide, whereas the less active variants R219I, R298H, and Y432S with the correct incoming nucleotide mimic WT pol κ with the incorrect incoming nucleotide. Thus, the observations from MD simulations suggest a possible explanation for the observed experimental results that pol κ adopts specific active and inactive conformations that depend on both the protein variant and the identity of the DNA adduct.

    View details for PubMedID 30004685

  • Bulky Lesion Bypass Requires Dpo4 Binding in Distinct Conformations SCIENTIFIC REPORTS Liyanage, P. S., Walker, A. R., Brenlla, A., Cisneros, G., Romano, L. J., Rueda, D. 2017; 7: 17383


    Translesion DNA synthesis is an essential process that helps resume DNA replication at forks stalled near bulky adducts on the DNA. Benzo[a]pyrene (B[a]P) is a polycyclic aromatic hydrocarbon (PAH) that can be metabolically activated to benzo[a]pyrene diol epoxide (BPDE), which then can react with DNA to form carcinogenic DNA adducts. Here, we have used single-molecule florescence resonance energy transfer (smFRET) experiments, classical molecular dynamics simulations, and nucleotide incorporation assays to investigate the mechanism by which the model Y-family polymerase, Dpo4, bypasses a (+)-cis-B[a]P-N 2-dG adduct in DNA. Our data show that when (+)-cis-B[a]P-N 2-dG is the templating base, the B[a]P moiety is in a non-solvent exposed conformation stacked within the DNA helix, where it effectively blocks nucleotide incorporation across the adduct by Dpo4. However, when the media contains a small amount of dimethyl sulfoxide (DMSO), the adduct is able to move to a solvent-exposed conformation, which enables error-prone DNA replication past the adduct. When the primer terminates across from the adduct position, the addition of DMSO leads to the formation of an insertion complex capable of accurate nucleotide incorporation.

    View details for PubMedID 29234107

  • ALKBH7 variant related to prostate cancer exhibits altered substrate binding Walker, A., Silvestrov, P., Muller, T., Podolski, R., Dyson, G., Hausinger, R., Cisneros, G. AMER CHEMICAL SOC. 2017
  • ALKBH7 Variant Related to Prostate Cancer Exhibits Altered Substrate Binding PLOS COMPUTATIONAL BIOLOGY Walker, A. R., Silvestrov, P., Mueller, T. A., Podolsky, R. H., Dyson, G., Hausinger, R. P., Cisneros, G. 2017; 13 (2): e1005345


    The search for prostate cancer biomarkers has received increased attention and several DNA repair related enzymes have been linked to this dysfunction. Here we report a targeted search for single nucleotide polymorphisms (SNPs) and functional impact characterization of human ALKBH family dioxygenases related to prostate cancer. Our results uncovered a SNP of ALKBH7, rs7540, which is associated with prostate cancer disease in a statistically significantly manner in two separate cohorts, and maintained in African American men. Comparisons of molecular dynamics (MD) simulations on the wild-type and variant protein structures indicate that the resulting alteration in the enzyme induces a significant structural change that reduces ALKBH7's ability to bind its cosubstrate. Experimental spectroscopy studies with purified proteins validate our MD predictions and corroborate the conclusion that this cancer-associated mutation affects productive cosubstrate binding in ALKBH7.

    View details for PubMedID 28231280

    View details for PubMedCentralID PMC5322872

  • Computational Simulations of DNA Polymerases: Detailed Insights on Structure/Function/Mechanism from Native Proteins to Cancer Variants. Chemical research in toxicology Walker, A. R., Cisneros, G. A. 2017; 30 (11): 1922–35


    Genetic information is vital in the cell cycle of DNA-based organisms. DNA polymerases (DNA Pols) are crucial players in transactions dealing with these processes. Therefore, the detailed understanding of the structure, function, and mechanism of these proteins has been the focus of significant effort. Computational simulations have been applied to investigate various facets of DNA polymerase structure and function. These simulations have provided significant insights over the years. This perspective presents the results of various computational studies that have been employed to research different aspects of DNA polymerases including detailed reaction mechanism investigation, mutagenicity of different metal cations, possible factors for fidelity synthesis, and discovery/functional characterization of cancer-related mutations on DNA polymerases.

    View details for PubMedID 28877429

    View details for PubMedCentralID PMC5696005

  • Investigating carbohydrate based ligands for galectin-3 with docking and molecular dynamics studies JOURNAL OF MOLECULAR GRAPHICS & MODELLING Walker, A. R., Bonomi, R., Popov, V., Gelovani, J. G., Cisneros, G. 2017; 71: 211–17


    Galectin-3 (Gal-3) is a carbohydrate binding protein that is overexpressed in several types of cancers, including pancreatic cancer, which makes it a good target for both imaging and therapeutic drug design. A ligand library specialized for 18F positron emission tomography (PET) has been investigated with molecular dynamics (MD) and free energy methods to determine the relative binding energies of various potential ligands. Our results suggest that traditional docking methods can give good results when complemented by molecular dynamics and free energy methods for these types of ligands. Available experimental binding affinities for a small number of the tested compounds show very good agreement with the calculated energies and provide the rational approach for design of Gal-3 ligands with even higher affinity.

    View details for PubMedID 27939933

  • LICHEM: A QM/MM Program for Simulations with Multipolar and Polarizable Force Fields JOURNAL OF COMPUTATIONAL CHEMISTRY Kratz, E. G., Walker, A. R., Lagardere, L., Lipparini, F., Piquemal, J., Cisneros, G. 2016; 37 (11): 1019–29


    We introduce an initial implementation of the LICHEM software package. LICHEM can interface with Gaussian, PSI4, NWChem, TINKER, and TINKER-HP to enable QM/MM calculations using multipolar/polarizable force fields. LICHEM extracts forces and energies from unmodified QM and MM software packages to perform geometry optimizations, single-point energy calculations, or Monte Carlo simulations. When the QM and MM regions are connected by covalent bonds, the pseudo-bond approach is employed to smoothly transition between the QM region and the polarizable force field. A series of water clusters and small peptides have been employed to test our initial implementation. The results obtained from these test systems show the capabilities of the new software and highlight the importance of including explicit polarization. © 2016 Wiley Periodicals, Inc.

    View details for PubMedID 26781073

    View details for PubMedCentralID PMC4808410

  • GPU-enabled binding free energy calculations of potential ligands for pancreatic cancer imaging Walker, A., Cisneros, G. AMER CHEMICAL SOC. 2016
  • Computational studies on potential PET imaging ligands for Galectin-3 in pancreatic cancer tumors Walker, A., Cisneros, G. AMER CHEMICAL SOC. 2015
  • Cycloaddition of ethene on a series of single-walled carbon nanotubes COMPUTATIONAL AND THEORETICAL CHEMISTRY Lawson, D. B., Walker, A. 2012; 981: 31–37