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

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Alchemical free energy methods are increasingly used in computer-aided drug discovery.
• Numerous methodologies exist for relative binding free energy (RBFE) calculations.
• Software and file format incompatibilities hinder the sharing of algorithms and protocols.

Purpose of the Study:

• To develop modular and interoperable RBFE workflows using the BioSimSpace framework.
• To assess the performance of community-developed setup, simulation, and analysis tools.
• To provide recommendations for best practices in applying RBFE methods for drug discovery.

Main Methods:

• Leveraged the BioSimSpace framework to construct RBFE workflows.
• Utilized a benchmark set of six protein-ligand congeneric series for assessment.
• Evaluated various community-developed tools for setup, simulation, and analysis.

Main Results:

• Demonstrated the creation of modular and interoperable RBFE workflows.
• Assessed the performance of different computational chemistry tools.
• Identified effective strategies for reliable RBFE calculations.

Conclusions:

• The BioSimSpace framework facilitates the development of standardized RBFE workflows.
• Performance assessment provides guidance for selecting appropriate tools.
• Recommendations are offered to enhance the reliability of RBFE methods in drug discovery.