Reproducibility of Free Energy Calculations across Different Molecular Simulation Software Packages

Area of Science:

• Computational Chemistry
• Molecular Modeling and Simulation

Background:

• Alchemical free energy calculations are crucial for predicting binding and solvation free energies.
• Software packages like AMBER, CHARMM, GROMACS, and SOMD support these calculations, but implementation variations exist.
• Reproducibility of relative alchemical free energy (RAFE) simulations, vital for drug discovery, requires thorough validation.

Purpose of the Study:

• To assess the reproducibility of relative alchemical free energy (RAFE) calculations across different simulation packages.
• To benchmark hydration free energies for small organic molecules using multiple computational codes.
• To provide reliable protocols for validating free energy calculation software.

Main Methods:

• Performed relative alchemical free energy (RAFE) calculations for hydration free energies of small organic molecules.
• Utilized established molecular simulation software: AMBER, CHARMM, GROMACS, and SOMD.
• Conducted absolute alchemical free energy simulations as a reference point.

Main Results:

• Achieved high reproducibility for hydration free energies, with results agreeing within approximately 0.2 kcal/mol across different software packages.
• Demonstrated that RAFE calculations can yield comparable results when meticulous attention is paid to package-specific protocols.
• Identified that no single universal protocol guarantees reproducibility across all tested codes.

Conclusions:

• Relative alchemical free energy (RAFE) simulations are reproducible across major molecular simulation software when protocols are carefully implemented.
• The reported benchmarks and protocols serve as a valuable resource for validating current and future free energy calculation software.
• Ensuring reproducibility requires careful attention to detail and adherence to package-specific simulation methodologies.