Publication Category: Molecular Dynamics and Statistical Thermodynamics

  • 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,

  • 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

  • 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).

  • 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

  • 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

  • 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,

  • 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

  • Water Networks Contribute to Enthalpy/Entropy Compensation in Protein–Ligand Binding

    J. Am. Chem. Soc. 2013, 135, 41, 15579–15584

    The mechanism (or mechanisms) of enthalpy–entropy (H/S) compensation in protein–ligand binding remains controversial, and there are still no predictive models (theoretical or experimental) in which hypotheses of ligand binding can be readily tested. Here we describe a particularly well-defined system of protein and ligands—human carbonic anhydrase (HCA) and a series of benzothiazole sulfonamide ligands with

  • Exploring Protein Flexibility: Incorporating Structural Ensembles From Crystal Structures and Simulation into Virtual Screening Protocols

    J. Phys. Chem. B 2012, 116, 23, 6952–6959

    The capacity of proteins to adapt their structure in response to various perturbations including covalent modifications, and interactions with ligands and other proteins plays a key role in biological processes. Here, we explore the ability of molecular dynamics (MD), replica exchange molecular dynamics (REMD), and a library of structures of crystal-ligand complexes, to sample the

  • Thermodynamic Analysis of Water Molecules at the Surface of Proteins and Applications to Binding Site Prediction and Characterization

    Proteins: Structure, Function, and Bioinformatics 80 (3), 871-883

    Water plays an essential role in determining the structure and function of all biological systems. Recent methodological advances allow for an accurate and efficient estimation of the thermodynamic properties of water molecules at the surface of proteins. In this work, we characterize these thermodynamic properties and relate them to various structural and functional characteristics of

  • Mechanism of the Hydrophobic Effect in the Biomolecular Recognition of Arylsulfonamides by Carbonic Anhydrase

    PNAS November 1, 2011 108 (44) 17889-17894

    Widely Cited

    The hydrophobic effect—a rationalization of the insolubility of nonpolar molecules in water—is centrally important to biomolecular recognition. Despite extensive research devoted to the hydrophobic effect, its molecular mechanisms remain controversial, and there are still no reliably predictive models for its role in protein–ligand binding. Here we describe a particularly well-defined system of protein and ligands—carbonic

  • Probing the α‐Helical Structural Stability of Stapled p53 Peptides: Molecular Dynamics Simulations and Analysis

    Chemical Biology & Drug Design, 75 (4), 348-359

    Widely Cited

    Reactivation of the p53 cell apoptosis pathway through inhibition of the p53‐hDM2 interaction is a viable approach to suppress tumor growth in many human cancers and stabilization of the helical structure of synthetic p53 analogs via a hydrocarbon cross‐link (staple) has been found to lead to increased potency and inhibition of protein–protein binding (J. Am.