Best Practices for Alchemical Free Energy Calculations

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 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.

Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors

“…We estimated potency of proposed designs and virtual synthetic libraries of analogs using alchemical free-energy calculations (34)(35)(36), an accurate physical modeling technique that has hitherto not been deployed in a high-throughput setup because of its prohibitive computational cost. We used Folding@home (37)-a worldwide distributed computing network where hundreds of thousands of volunteers around the world contributed computing power to create the world's first exascale computing resource (38)to compute the free energy of binding of all 20,000+ crowdsourced and internal design submissions using the Open Force Field Initiative "Parsley" small-molecule force fields (39) and nonequilibrium switching with the open source PERSES alchemical free-energy toolkit (40)(41)(42) based on the graphics processing unit (GPU)-accelerated OpenMM framework (38,43) (see Materials and methods).…”

Condensed-phase molecular representation to link structure and thermodynamics in molecular dynamics

“…We calculated the partitioning free energies by successively coupling the Van der Waals and electrostatic interactions between each compound and a pure water environment, as well as two systems containing a CL and a PG membrane, respectively [42][43][44]. We applied 40 intermediate coupling steps for each interaction type to ensure adequate sampling.…”

End-to-end differentiable construction of molecular mechanics force fields

“…5f shows the ligand heavy-atom RMSD aer aligning on protein heavy atoms for 0.5 ns trajectories of the Tyk2 : inhibitor system from the Alchemical Best Practices Benchmark Set 1.0. 105 It is readily apparent that the espaloma-derived parameters lead to trajectories that are comparably stable to simulations that utilize the Amber ff14SB protein force eld 106 with GAFF 1.81, GAFF 2.11, 26,27 or OpenFF 1.2.0 (ref. 56) small molecule force elds.…”