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Markov state models (MSMs) have been widely applied to study the kinetics and pathways of protein conformational dynamics based on statistical analysis of molecular dynamics (MD) simulations. These MSMs coarse-grain both configuration space and time in ways that limit what kinds of observables they can reproduce with high fidelity over different spatial and te…

The SARS-CoV-2 main viral protease (Mpro) is an attractive target for antivirals given its distinctiveness from host proteases, essentiality in the viral life cycle and conservation across coronaviridae. We launched the COVID Moonshot initiative to rapidly develop patent-free antivirals with open science and open data. Here we report the use of machine learnin…

An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape^1-3, have activity against diverse sarbecoviruses^4-7, and be highly protective through viral neutralization^8-11 and effector functions^12,13. Understanding how these properties relate to each other and vary across epitopes would aid the development…

Alchemical free energy calculations are a useful tool for predicting free energy differences associated with the transfer of molecules from one environment to another. The hallmark of these methods is the use of “bridging” potential energy functions representing alchemical intermediate states that cannot exist as real chemical species. The data collecte…

Cyclin-dependent kinases 4 and 6 (CDK4/6), represent a major therapeutic vulnerability for breast cancer. The kinases are clinically targeted via ATP competitive inhibitors (CDK4/6i); however, drug resistance commonly emerges over time. To understand CDK4/6i resistance, we surveyed over 1,300 breast cancers and identify several genetic alterations (e.g. FAT1, …

We present a methodology for defining and optimizing a general force field for classical molecular simulations, and we describe its use to derive the Open Force Field 1.0.0 small-molecule force field, codenamed Parsley. Rather than using traditional atom typing, our approach is built on the SMIRKS-native Open Force Field (SMIRNOFF) parameter assignment formali…

The computation of tautomer ratios of druglike molecules is enormously important in computer-aided drug discovery, as over a quarter of all approved drugs can populate multiple tautomeric species in solution. Unfortunately, accurate calculations of aqueous tautomer ratios-the degree to which these species must be penalized in order to correctly account for tau…

The goal of the Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL) challenge is to improve the accuracy of current computational models to estimate free energy of binding, deprotonation, distribution and other associated physical properties that are useful for the design of new pharmaceutical products. New experimental datasets of physicoch…

Protein kinase inhibitors are potent anticancer therapeutics. For example, the Bcr-Abl kinase inhibitor imatinib decreases mortality for chronic myeloid leukemia by 80%, but 22 to 41% of patients acquire resistance to imatinib. About 70% of relapsed patients harbor mutations in the Bcr-Abl kinase domain, where more than a hundred different mutations have been …

Community efforts in the computational molecular sciences (CMS) are evolving toward modular, open, and interoperable interfaces that work with existing community codes to provide more functionality and composability than could be achieved with a single program. The Quantum Chemistry Common Driver and Databases (QCDB) project provides such capability through an…