Automated Adaptive Absolute Binding Free Energy Calculations

Journal of Chemical Theory and Computation, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 10, 2024

Alchemical absolute binding free energy (ABFE) calculations have substantial potential in drug discovery, but are often prohibitively computationally expensive. To unlock their potential, efficient automated ABFE workflows required to reduce both computational cost and human intervention. We present a fully workflow based on the selection of λ windows, ensemble-based detection equilibration, adaptive allocation sampling time inter-replicate statistics. find that intermediate states with consistent overlap is rapid, robust, simple implement. Robust equilibration achieved paired

Language: Английский

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Multiple Topology Replica Exchange of Expanded Ensembles for Multidimensional Alchemical Calculations

Journal of Chemical Theory and Computation, Journal Year: 2025, Volume and Issue: 21(1), P. 230 - 240

Published: Jan. 2, 2025

Relative free energy (RFE) calculations are now widely used in academia and the industry, but their accuracy is often limited by poor sampling of complexes' conformational ensemble. To help address problems when simulating many relative binding energies, we developed a novel method termed multiple topology replica exchange expanded ensembles (MT-REXEE). This enables parallel ensemble calculations, facilitating iterative RFE computations while allowing between transformations. These transformations can be adaptable to any set systems with common backbone or central substructure. We demonstrate that MT-REXEE maintains thermodynamic cycle closure same extent as standard for both solvation calculations. The tested involve incorporate diverse heavy atoms multisite perturbations small molecule core resembling λ dynamics, without necessitating modifications MD code. Our initial implementation GROMACS. outline systematic approach setup provide instructions on how perform inter-replica coordinate modifications. work shows accurate reproducible estimates prompts expansion more complex test other molecular dynamics simulation infrastructures.

Language: Английский

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Adaptive Lambda Scheduling: A Method for Computational Efficiency in Free Energy Perturbation Simulations

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 9, 2025

Recent increases in the availability of computational power have improved accessibility ligand–protein relative binding free energy (RBFE) calculations; however, these calculations remain resource-intensive, which can limit their practical application. RBFE typically use a set thermodynamic intermediates mediated by transformation coordinate λ. Optimizing λ offers way to tune efforts required for given calculation. Here, we present Adaptive Lambda Scheduling (ALS), streamlined approach on-the-fly bespoke scheduling. We show it achieve substantial reductions cost while retaining predictive performance.

Language: Английский

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FEP-SPell-ABFE: An Open-Source Automated Alchemical Absolute Binding Free-Energy Calculation Workflow for Drug Discovery

Journal of Chemical Information and Modeling, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

The binding affinity between a drug molecule and its target, measured by the absolute free energy (ABFE), is crucial factor in lead discovery phase of development. Recent research has highlighted potential silico ABFE predictions to directly aid development allowing for ranking prioritization promising candidates. This work introduces an open-source Python workflow called FEP-SPell-ABFE, designed automate calculations with minimal user involvement. requires only three key inputs: receptor protein structure PDB format, candidate ligands SDF configuration file (config.yaml) that governs both molecular dynamics simulation parameters. It produces ranked list along their energies comma-separated values (CSV) format. leverages SLURM (Simple Linux Utility Resource Management) automating task execution resource allocation across modules. A usage example several benchmark systems validation are provided. FEP-SPell-ABFE workflow, practical example, publicly accessible on GitHub at https://github.com/freeenergylab/FEP-SPell-ABFE, distributed under MIT License.

Language: Английский

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Automated Adaptive Absolute Binding Free Energy Calculations

Published: June 18, 2024

Alchemical absolute binding free energy (ABFE) calculations have substantial potential in drug discovery, but are often prohibitively computationally expensive. To unlock their potential, efficient automated ABFE workflows required to reduce both computational cost and human intervention. We present a fully-automated workflow based on the selection of λ windows, ensemble-based detection equilibration, adaptive allocation sampling time inter-replicate statistics. find that intermediate states with consistent overlap is rapid, robust, simple implement. Robust equilibration achieved paired t-test between estimates at initial final portions an ensemble runs. determine reasonable default parameters for all algorithms show full produces equivalent results non-adaptive scheme over variety test systems, while accelerating equilibration. Our complete implemented open-source package A3FE (https://github.com/michellab/a3fe).

Language: Английский

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Improvements in Precision of Relative Binding Free Energy Calculations Afforded by the Alchemical Enhanced Sampling (ACES) Approach

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(18), P. 7046 - 7055

Published: Sept. 3, 2024

Accurate

Language: Английский

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