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

• Published in: Journal of chemical information and modeling 2024-09, Vol.64 (18), p.7046-7055
• Main Authors: Tsai, Hsu-Chun, Xu, James, Guo, Zhenyu, Yi, Yinhui, Tian, Chuan, Que, Xinyu, Giese, Timothy, Lee, Tai-Sung, York, Darrin M., Ganguly, Abir, Pan, Albert
• Format: Article
• Language: English
• Subjects: Binding; Binding energy; Computational Chemistry; Drug Discovery - methods; Free energy; Ligands; Molecular Dynamics Simulation; Protein Binding; Proteins; Proteins - chemistry; Proteins - metabolism; Sampling; Small Molecule Libraries - chemistry; Small Molecule Libraries - metabolism; Thermodynamics
• ISSN: 1549-9596; 1549-960X; 1549-960X
• DOI: 10.1021/acs.jcim.4c00464

Accurate in silico predictions of how strongly small molecules bind to proteins, such as those afforded by relative binding free energy (RBFE) calculations, can greatly increase the efficiency of the hit-to-lead and lead optimization stages of the drug discovery process. The success of such calculations, however, relies heavily on their precision. Here, we show that a recently developed alchemical enhanced sampling (ACES) approach can consistently improve the precision of RBFE calculations on a large and diverse set of proteins and small molecule ligands. The addition of ACES to conventional RBFE calculations lowered the average hysteresis by over 35% (0.3–0.4 kcal/mol) and the average replicate spread by over 25% (0.2–0.3 kcal/mol) across a set of 10 protein targets and 213 small molecules while maintaining similar or improved accuracy. We show in atomic detail how ACES improved convergence of several representative RBFE calculations through enhancing the sampling of important slowly transitioning ligand degrees of freedom.