Best Practices for Alchemical Free Energy Calculations

TL;DR

This paper reviews best practices for alchemical free energy calculations, emphasizing the importance of careful methodology to ensure accurate, reproducible results in predicting molecular transfer free energies, especially in drug discovery.

Contribution

It provides a comprehensive overview of current best practices for alchemical free energy calculations across various application domains.

Findings

Guidelines for avoiding common pitfalls in free energy calculations

Recommendations for ensuring reproducibility and accuracy

Discussion of corrections needed for experimental comparison

Abstract

Alchemical free energy calculations are a useful tool for predicting free energy differences associated with the transfer of molecules from one environment to another. The hallmark of these methods is the use of "bridging" potential energy functions representing \emph{alchemical} intermediate states that cannot exist as real chemical species. The data collected from these bridging alchemical thermodynamic states allows the efficient computation of transfer free energies (or differences in transfer free energies) with orders of magnitude less simulation time than simulating the transfer process directly. While these methods are highly flexible, care must be taken in avoiding common pitfalls to ensure that computed free energy differences can be robust and reproducible for the chosen force field, and that appropriate corrections are included to permit direct comparison with experimental data. In this paper, we review current best practices for several popular application domains of alchemical free energy calculations, including relative and absolute small molecule binding free energy calculations to biomolecular targets.