Obtaining accurate binding free energies from in silico screens has been a long-standing goal for the computational chemistry community. However, accuracy and cost are at odds with one another, limiting utility of methods that perform this type calculation. Many achieve massive scale by explicitly or implicitly assuming target protein adopts single structure, undergoes limited fluctuations around to minimize cost. Others simulate each protein–ligand complex interest, accepting lower...

X-ray crystallography is the gold standard to resolve conformational ensembles that are significant for protein function, ligand discovery, and computational methods development. However, relevant states may be missed at common cryogenic (cryo) data-collection temperatures but can populated room temperature. To assess impact of temperature on making structural discoveries, we systematically investigated changes in response binding a workhorse, T4 lysozyme L99A cavity. Despite decades work...

Part of early stage drug discovery involves determining how molecules may bind to the target protein. Through understanding where and bind, chemists can begin build ideas on design improvements increase binding affinities. In this retrospective study, we compare computational approaches like docking, molecular dynamics (MD) simulations, a non-equilibrium candidate Monte Carlo (NCMC)-based method (NCMC + MD) perform in predicting modes for set 12 fragment-like molecules, which soluble epoxide...

Part of early stage drug discovery involves determining how molecules may bind to the target protein. Through understanding where and bind, chemists can begin build ideas on design improvements increase binding affinities. In this retrospective study, we compare computational approaches like docking, molecular dynamics (MD) simulations, a non-equilibrium candidate Monte Carlo (NCMC) based method (NCMC+MD) perform in predicting modes for set 12 fragment-like which soluble epoxide hydrolase....

As a model system, the binding pocket of L99A mutant T4 lysozyme has been subject numerous computational free energy studies. However, some previous studies have failed to fully sample and account for observed changes in upon congeneric ligand series, limiting accuracy results. In this work, we establish definitions conformational states based on dynamics system rather than from experimental crystal structures. Using these definitions, estimate timescales transitions between protein, which...

As a model system, the binding pocket of L99A mutant T4 lysozyme has been subject numerous computational free energy studies. However, previous studies have failed to fully sample and account for observed changes in upon congeneric ligand series, limiting accuracy results. In this work, we resolve closed, intermediate, open states previously reported experiment MD establish definitions these based on dynamics system. From analysis, arrive at two primary conclusions. First, assignment...

Physics-based methods such as protein-ligand binding free energy calculations have been increasingly adopted in early-stage drug discovery to prioritize promising compounds for synthesis. However, the accuracy of these is highly dependent on details calculation and choices made while preparing ligands protein ahead running calculations. During ligand preparation, researchers typically assign partial atomic charges each atom using a specific conformation charge assignment, often input...

Abstract Obtaining accurate binding free energies from in silico screens has been a longstanding goal for the computational chemistry community. However, accuracy and cost are at odds with one another, limiting utility of methods that perform this type calculation. Many achieve massive scale by explicitly or implicitly assuming target protein adopts single structure, undergoes limited fluctuations around to minimize cost. Others simulate each protein-ligand complex interest, accepting lower...

<div>Part of early stage drug discovery involves determining how molecules may bind to the target protein. Through understanding where and bind, chemists can begin build ideas on design improvements increase binding affinities. In this retrospective study, we compare computational approaches like docking, molecular dynamics (MD) simulations, a non-equilibrium candidate Monte Carlo (NCMC) based method (NCMC+MD) perform in predicting modes for set 12 fragment-like which soluble epoxide...

Part of early stage drug discovery involves determining how molecules may bind to the target protein. Through understanding where and bind, chemists can begin build ideas on design improvements increase binding affinities. In this retrospective study, we compare computational approaches like docking, molecular dynamics (MD) simulations, a non-equilibrium candidate Monte Carlo (NCMC) based method (NCMC+MD) perform in predicting modes for set 12 fragment-like which soluble epoxide hydrolase....