Biomolecular simulations are typically performed in an aqueous environment where the number of ions remains fixed for duration simulation, generally with either a minimally neutralizing ion or salt pairs intended to match macroscopic concentration. In contrast, real biomolecules experience local environments concentration is dynamic and may differ from bulk. The degree variability average deviation remains, as yet, unknown. Here, we describe theory implementation Monte Carlo osmostat that...

Abstract Alchemical free energy methods with molecular mechanics (MM) force fields are now widely used in the prioritization of small molecules for synthesis structure-enabled drug discovery projects because their ability to deliver 1–2 kcal mol −1 accuracy well-behaved protein-ligand systems. Surpassing this limit would significantly reduce number compounds that must be synthesized achieve desired potencies and selectivities design campaigns. However, MM pose a challenge achieving higher...

Graph neural network-based continuous embedding is used to replace a human expert-derived discrete atom typing scheme parametrize accurate and extensible molecular mechanics force fields.

Alchemical free energy methods using molecular mechanics (MM) force fields are essential tools for predicting thermodynamic properties of small molecules, especially via calculations that can estimate quantities relevant drug discovery such as affinities, selectivities, the impact target mutations, and ADMET properties. While traditional MM forcefields rely on hand-crafted, discrete atom types parameters, modern approaches based graph neural networks (GNNs) learn continuous embedding vectors...

Accurately predicting protein–ligand binding affinities and modes is a major goal in computational chemistry, but even the prediction of ligand proteins poses challenges. Here, we focus on solving mode problem for rigid fragments. That is, computing dominant placement, conformation, orientations relatively rigid, fragment-like receptor, populations multiple which may be relevant. This important its own right, more timely given recent success alchemical free energy calculations. Alchemical...

The computation of tautomer ratios druglike molecules is enormously important in computer-aided drug discovery, as over a quarter all approved drugs can populate multiple tautomeric species solution. Unfortunately, accurate calculations aqueous ratios-the degree to which these must be penalized order correctly account for tautomers modeling binding discovery-is surprisingly difficult. While quantum chemical approaches computing using continuum solvent models and rigid-rotor...

While Langevin integrators are popular in the study of equilibrium properties complex systems, it is challenging to estimate timestep-induced discretization error: degree which sampled phase-space or configuration-space probability density departs from desired target due use a finite integration timestep. Sivak et al., introduced convenient approach approximating natural measure error between and density, Kullback-Leibler (KL) divergence, phase space, but did not specifically address issue...

Molecular mechanics force fields define how the energy and forces in a molecular system are computed from its atomic positions, thus enabling study of such systems through computational methods like dynamics Monte Carlo simulations. Despite progress toward automated field parametrization, considerable human expertise is required to develop or extend fields. In particular, input has long been atom types, which encode chemically unique environments that determine parameters will be assigned....

Abstract The computation of tautomer ratios druglike molecules is enormously important in computer-aided drug discovery, as over a quarter all approved drugs can populate multiple tautomeric species solution. Unfortunately, accurate calculations aqueous ratios—the degree to which these must be penalized order correctly account for tautomers modeling binding discovery—is surprisingly diffcult. While quantum chemical approaches computing using continuum solvent models and rigid-rotor...

Abstract Alchemical free energy calculations are an important tool in the computational chemistry toolbox, enabling efficient calculation of quantities critical for drug discovery such as ligand binding affinities, selectivities, and partition coefficients. However, modern alchemical suffer from three significant limitations: (1) molecular mechanics force fields limited their ability to model complex interactions, (2) classical unable treat phenomena that involve rearrangements chemical...

A high level of physical detail in a molecular model improves its ability to perform accuracy simulations but can also significantly affect complexity and computational cost. In some situations, it is worthwhile add capture properties interest; others, additional unnecessary make computationally infeasible. this work, we demonstrate the use Bayesian inference for selection, using Monte Carlo sampling techniques accelerated with surrogate modeling evaluate Bayes factor evidence different...

Atomic partial charges are crucial parameters for Molecular Dynamics (MD) simulations, molecular mechanics calculations, and virtual screening, as they determine the electrostatic contributions to interaction energies. Current methods calculating charges, however, either slow scale poorly with size (quantum chemical methods) or unreliable (empirical methods). Here, we present a new charge derivation method based on Graph Nets---a set of update aggregate functions that operate topologies...

Abstract Accurate molecular mechanics force fields for small molecules are essential predicting protein-ligand binding affinities in drug discovery and understanding the biophysics of biomolecular systems. Torsion potentials derived from quantum chemical (QC) calculations critical determining conformational distributions molecules, but computationally expensive scale poorly with size. To reduce computational cost avoid complications distal through-space intramolecular interactions, generally...

Molecular mechanics force fields define how the energy and forces of a molecular system are computed from its atomic positions, enable study such systems through computational methods like dynamics Monte Carlo simulations. Despite progress toward automated field parameterization, considerable human expertise is required to develop or extend fields. In particular, input has long been atom types , which encode chemically unique environments that determine parameters must be assigned. However,...

Abstract Biomolecular simulations are typically performed in an aqueous environment where the number of ions remains fixed for duration simulation, generally with either a minimally neutralizing ion or salt pairs intended to match macroscopic concentration. In contrast, real biomolecules experience local environments concentration is dynamic and may differ from bulk. The degree variability average deviation remains, as yet, unknown. Here, we describe theory implementation Monte Carlo...

Abstract While Langevin integrators are popular in the study of equilibrium properties complex systems, it is challenging to estimate timestep-induced discretization error: degree which sampled phase-space or configuration-space probability density departs from desired target due use a finite integration timestep. In [1], Sivak et al . introduced convenient approach approximating natural measure error between and density, KL divergence, phase space , but did not specifically address issue...

Engineered macromolecules offer compelling means for the therapy of conventionally undruggable interactions in human disease. However, their efficacy is limited by barriers to tissue and intracellular delivery. Inspired recent advances molecular barcoding evolution, we developed BarcodeBabel, a generalized method design libraries peptide barcodes suitable high-throughput mass spectrometry proteomics. Combined with PeptideBabel, Monte Carlo sampling algorithm peptides evolvable...

Accurately predicting protein-ligand binding is a major goal in computational chemistry, but even the prediction of ligand modes proteins poses challenges. Here, we focus on solving mode problem for rigid fragments. That is, computing dominant placement, conformation, and orientations relatively rigid, fragment-like receptor, populations multiple which may be relevant. This important its own right, more timely given recent success alchemical free energy calculations. Alchemical calculations...

<div>Molecular mechanics force fields define how the energy and forces of a molecular system are computed from its atomic positions, enable study such systems through computational methods like dynamics Monte Carlo simulations. Despite progress toward automated field parameterization, considerable human expertise is required to develop or extend fields. </div><div>In particular, input has long been <i>atom types</i>, which encode chemically unique environments...

A high level of physical detail in a molecular model improves its ability to perform accuracy simulations, but can also significantly affect complexity and computational cost. In some situations, it is worthwhile add additional capture properties interest; others, unnecessary make simulations computationally infeasible. this work we demonstrate the use Bayes factors for selection, using Monte Carlo sampling techniques evaluate evidence different levels two-centered Lennard-Jones + quadrupole...