Lambda-ABF-OPES: Faster Convergence with High Accuracy in Alchemical Free Energy Calculations

2025/02/24 by Narjes Ansari, Zhifeng Francis Jing, Zhifeng Jing +7 · 1 voice · 4 citations
Biochemistry, Genetics and Molecular Biology · Materials Science · Computer Science · #Protein Structure and Dynamics #Machine Learning in Materials Science #Computational Drug Discovery Methods

paper · pdf · doi:10.1021/acs.jpclett.5c00683

Abstract

Predicting the binding affinity between small molecules and target macromolecules while combining both speed and accuracy is a cornerstone of modern computational drug discovery, which is critical for accelerating therapeutic development. Despite recent progress in molecular dynamics (MD) simulations, such as advanced polarizable force fields and enhanced sampling techniques, estimating absolute binding free energies (ABFEs) remains computationally challenging. To overcome these difficulties, we introduce a highly efficient hybrid methodology that couples the Lambda-adaptive biasing force (Lambda-ABF) scheme with on-the-fly probability enhanced sampling (OPES). This approach achieves up to a 9-fold improvement in sampling efficiency and computational speed compared to the original Lambda-ABF when used in conjunction with the AMOEBA polarizable force field, yielding converged results at a fraction of the cost of standard techniques.

Citations

• Nonphysical sampling distributions in Monte Carlo free-energy estimation: Umbrella sampling
• Enhanced Sampling with Machine Learning
• Water–glycan interactions drive the SARS-CoV-2 spike dynamics: insights into glycan-gate control and camouflage mechanisms

Cited by

• The Convergence Frontier: Integrating Machine Learning and High Performance Quantum Computing for Next-Generation Drug Discovery
• Dual-LAO for calculating fast and robust relative binding free energies of simple and complex transformations
• Practical protein-pocket hydration-site prediction for drug discovery on a quantum computer
• Calculating Free-Energy Differences Using an Average Force: A Tutorial for Adaptive Biasing Force Simulations

Discussions

• ‪#compchem New group preprint:"Lambda-ABF-OPES: Faster Convergence with High Accuracy in Alchemical Free Energy Calculations" Converged free energy results at a fraction of the cost of standard techni [bsky, 10 points, 0 comments]

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