All Scientific Publications

  • Adjuvant-Pulsed mRNA Vaccine Nanoparticle for Immunoprophylactic and Therapeutic Tumor Suppression in Mice

    Biomaterials, 2020, 120431

    Synthetic mRNA represents an exciting cancer vaccine technology to the implementation of effective cancer immunotherapy. However, inefficient in vivo mRNA delivery along with a requirement for immune co-stimulation present major hurdles to achieving anti-tumor therapeutic efficacy. Here, we demonstrate a proof-of-concept adjuvant-pulsed mRNA vaccine nanoparticle (NP) that is composed of an ovalbumin-coded mRNA and a palmitic

  • Accounting for the Central Role of Interfacial Water in Protein-Ligand Binding Free Energy Calculations

    ChemRxiv. Preprint.

    Rigorous binding free energy methods in drug discovery are growing in popularity due to a combination of methodological advances, improvements in computer hardware, and workflow automation. These calculations typically use molecular dynamics (MD) to sample from the Boltzmann distribution of conformational states. However, when part or all the binding site is inaccessible to bulk solvent,

  • Lipidation Approaches Potentiate Adjuvant-Pulsed Immune Surveillance: A Design Rationale for Cancer Nanovaccine

    Bioeng. Biotechnol., 8 2020, 787

    Adjuvant-pulsed peptide vaccines hold great promise for the prevention and treatment of different diseases including cancer. However, it has been difficult to maximize vaccine efficacy due to numerous obstacles including the unfavorable tolerability profile of adjuvants, instability of peptide antigens, limited cellular uptake, and fast diffusion from the injection site, as well as systemic adverse

  • Rigorous Free Energy Simulations in Virtual Screening

    J. Chem. Inf. Model. 2020

    Most Read

    Virtual high throughput screening (vHTS) in drug discovery is a powerful approach to identify hits: when applied successfully, it can be much faster and cheaper than experimental high-throughput screening approaches. However, mainstream vHTS tools have significant limitations: ligand-based methods depend on knowledge of existing chemical matter, while structure-based tools such as docking involve significant approximations

  • Mechanism of Biomolecular Recognition of Trimethyllysine by the Fluorinated Aromatic Cage of KDM5A PHD3 Finger

    Commun Chem 3 (1), 1-12

    The understanding of biomolecular recognition of posttranslationally modified histone proteins is centrally important to the histone code hypothesis. Despite extensive binding and structural studies on the readout of histones, the molecular language by which posttranslational modifications on histone proteins are read remains poorly understood. Here we report physical-organic chemistry studies on the recognition of the

  • ATP-driven Non-equilibrium Activation of Kinase Clients by the Molecular Chaperone Hsp90

    bioRxiv 2020

    The molecular chaperone 90-kDa heat-shock protein (Hsp90) assists the late-stage folding and activation of diverse types of protein substrates (called clients), including many kinases. Previous studies have established that the Hsp90 homodimer undergoes an ATP-driven cycle through open and closed conformations. Here I propose a model of client activation by Hsp90, which predicts that this

  • Improved Alchemical Free Energy Calculations with Optimized Smoothstep Softcore Potentials

    Progress in the development of GPU-accelerated free energy simulation software has enabled practical applications on complex biological systems and fueled efforts to develop more accurate and robust predictive methods. In particular, this work re-examines concerted (a.k.a., single-step or unified) alchemical transformations com- monly used in the prediction of hydration and relative binding free energies (RBFE).

  • Fully Integrated FPGA Molecular Dynamics Simulations

    SC ’19, November 17–22

    The implementation of Molecular Dynamics (MD) on FPGAs has received substantial attention. Previous work, however, has consisted of either proof-of-concept implementations of components, usually the range-limited force; full systems, but with much of the work shared by the host CPU; or prototype demonstrations, e.g., using OpenCL, that neither implement a whole system nor have competitive

  • Optimal Measurement Network of Pairwise Differences

    J. Chem. Inf. Model. 2019, 59, 11, 4720–4728

    When both the difference between two quantities and their individual values can be measured or computationally predicted, multiple quantities can be determined from the measurements or predictions of select individual quantities and select pairwise differences. These measurements and predictions form a network connecting the quantities through their differences. Here, I analyze the optimization of such

  • Molecular Dynamics Range-Limited Force Evaluation Optimized for FPGAs

    2019 IEEE 30th International Conference on ASAP

    FPGA Molecular Dynamics was much studied from 2004-2010. Due to limited chip resources of that era, and the inherent variety and complexity of tasks comprising Molecular Dynamics simulations (MD), those FPGA accelerators relied on host or embedded processors to organize and pre-process input and output data. This introduced long latency for data movement between simulation

  • Finite-Sample Bias in Free Energy Bridge Estimators

    J. Chem. Phys. 151, 034105 (2019)

    In practical free energy estimation, the bias is often neglected once it has been shown to vanish in the large-sample limit. Yet finite-sample bias always exists and ought to be considered in any rigorous study. This work develops a metric for bias in a broad class of free energy “bridge estimators” (e.g., Bennett’s method). The

  • Molecular Simulations Minimally Restrained by Experimental Data

    J. Chem. Phys. 150, 154121 (2019)

    One popular approach to incorporating experimental data into molecular simulations is to restrain the ensemble average of observables to their experimental values. Here, I derive equations for the equilibrium distributions generated by restrained ensemble simulations and the corresponding expected values of observables. My results suggest a method to restrain simulations so that they generate distributions

  • Protonation States and Conformations of Inositol and Phosphoinositol Phosphates from Molecular Simulations

    Biophysical Journal 116 (3), 506a-507a

    Phosphoinositide phosphates (PIPs) are ubiquitous components in numerous cell signaling pathways. However, there is currently a considerable lack of detailed atomistic models for how PIPs interact with their environment, especially with kinase and phosphatase proteins. While it is well- documented that molecular recognition of PIPs depends on the specific num- ber of phosphorylated sites (one

  • Cochaperones Enable Hsp70 to Use ATP Energy for Non-Equilibrium Sta- bilization of Native Proteins

    Biophysical Journal 116 (3), 339a

    The heat shock protein 70 (Hsp70) chaperones, vital to the proper folding of proteins inside cells, consume ATP and require cochaperones in assisting pro- tein folding. It is unclear whether Hsp70 can utilize the free energy from ATP hydrolysis to fold a protein into a native state that is thermodynamically unsta- ble in the chaperone-free

  • A Variational Linear-Scaling Framework to Build Practical, Efficient Next-Generation Orbital-Based Quantum Force Fields

    J. Chem. Theory Comput. 2013, 9, 3, 1417–1427

    We introduce a new hybrid molecular orbital/density-functional modified divide-and-conquer (mDC) approach that allows the linear-scaling calculation of very large quantum systems. The method provides a powerful framework from which linear-scaling force fields for molecular simulations can be developed. The method is variational in the energy and has simple, analytic gradients and essentially no break-even point

  • On the Rational Design of Zeolite Clusters for Converging Reaction Barriers: Quantum Study of Aldol Kinetics Confined in HZSM-5

    J. Phys. Chem. C 2018, 122, 40, 23230–23241

    We have performed density functional theory calculations to investigate the convergence of reaction barriers with respect to zeolite cluster size, for multistep reactions catalyzed in HZSM-5. We constructed cluster models of HZSM-5 using the delta-cluster approach reported previously by us. We then computed barriers for different reaction types to determine the cluster sizes and neighbor-list

  • Relative Binding Free Energy Calculations in Drug Discovery: Recent Advances and Practical Considerations

    J. Chem. Inf. Model. 2017, 57, 12, 2911–2937

    Most ReadWidely Cited

    Accurate in silico prediction of protein–ligand binding affinities has been a primary objective of structure-based drug design for decades due to the putative value it would bring to the drug discovery process. However, computational methods have historically failed to deliver value in real-world drug discovery applications due to a variety of scientific, technical, and practical challenges. Recently,

  • A Water-Bridged Cysteine-Cysteine Redox Regulation Mechanism in Bacterial Protein Tyrosine Phosphatases

    Chem 3 (4), 665-677

    The emergence of multidrug-resistant Mycobacterium tuberculosis(Mtb) strains highlights the need to develop more efficacious and potent drugs. However, this goal is dependent on a comprehensive understanding of Mtb virulence protein effectors at the molecular level. Here, we used a post-expression cysteine (Cys)-to-dehydrolanine (Dha) chemical editing strategy to identify a water-mediated motif that modulates accessibility of the protein tyrosinephosphatase A (PtpA) catalytic pocket.

  • OpenCL for HPC With FPGAs: Case Study in Molecular Electrostatics

    2017 IEEE HPEC

    FPGAs have emerged as a cost-effective accelerator alternative in clouds and clusters. Programmability remains a challenge, however, with OpenCL being generally recognized as a likely part of the solution. In this work we seek to advance the use of OpenCL for HPC on FPGAs in two ways. The first is by examining a core HPC

  • Identification of a Novel Class of BRD4 Inhibitors by Computational Screening and Binding Simulations

    ACS Omega 2017, 2, 8, 4760–4771

    Computational screening is a method to prioritize small-molecule compounds based on the structural and biochemical attributes built from ligand and target information. Previously, we have developed a scalable virtual screening workflow to identify novel multitarget kinase/bromodomain inhibitors. In the current study, we identified several novel N-[3-(2-oxo-pyrrolidinyl)phenyl]-benzenesulfonamide derivatives that scored highly in our ensemble docking protocol. We

  • The Hsp70 Interdomain Linker Is a Dynamic Switch That Enables Allosteric Communication Between Two Structured Domains

    Journal of Biological Chemistry 292 (36), 14765-14774

    Hsp70 molecular chaperones play key roles in cellular protein homeostasis by binding to exposed hydrophobic regions of incompletely folded or aggregated proteins. This crucial Hsp70 function relies on allosteric communication between two well-structured domains: an N-terminal nucleotide-binding domain (NBD) and a C-terminal substrate-binding domain (SBD), which are tethered by an interdomain linker. ATP or ADP

  • Deciphering Cryptic Binding Sites on Proteins by Mixed-Solvent Molecular Dynamics

    J. Chem. Inf. Model. 2017, 57, 6, 1388–1401

    In recent years, molecular dynamics simulations of proteins in explicit mixed solvents have been applied to various problems in protein biophysics and drug discovery, including protein folding, protein surface characterization, fragment screening, allostery, and druggability assessment. In this study, we perform a systematic study on how mixtures of organic solvent probes in water can reveal

  • Improving Force Field Parameters for Small‐Molecule Conformation Generation

    Computational Pharmaceutical Solid State Chemistry, 57

    This chapter focuses on conformations of small molecules of the size of typical drug-like molecules (molecular weight <500 Da) with the aim of accurately predicting conformations, which could then be used as inputs for polymorph prediction programs. Physics-based molecular mechanics force fields are used to generate low-energy conformations, independent of the crystal packing environment, and

  • Large-Scale Computational Screening Identifies First in Class Multitarget Inhibitor of EGFR Kinase and BRD4

    Sci Rep 5, 16924

    Inhibition of cancer-promoting kinases is an established therapeutic strategy for the treatment of many cancers, although resistance to kinase inhibitors is common. One way to overcome resistance is to target orthogonal cancer-promoting pathways. Bromo and Extra-Terminal (BET) domain proteins, which belong to the family of epigenetic readers, have recently emerged as promising therapeutic targets in

  • Chemical Basis for the Recognition of Trimethyllysine by Epigenetic Reader Proteins

    Nat Commun 6 (1), 1-12

    A large number of structurally diverse epigenetic reader proteins specifically recognize methylated lysine residues on histone proteins. Here we describe comparative thermodynamic, structural and computational studies on recognition of the positively charged natural trimethyllysine and its neutral analogues by reader proteins. This work provides experimental and theoretical evidence that reader proteins predominantly recognize trimethyllysine via