Modular and Interoperable Workflows for Benchmarking Alchemical Binding Free Energy Calculation Methodologies

Alchemical free energy methods are gaining traction in computer-aided drug discovery. An expanding array of methodologies is available for the setup, execution, and analysis of relative binding free energy (RBFE) calculations. However, the sharing of algorithms and protocols developed by different organizations is often impeded by incompatible software and outdated file formats. In this work, we leveraged the BioSimSpace framework to build modular and interoperable RBFE workflows. We assessed the performance of various setup, simulation, and analysis tools developed by the community on a benchmark set of six protein-ligand congeneric series, providing recommendations on best practices for the reliable application of RBFE methods in drug discovery.