The Open Free Energy Consortium: Alchemistry for Everyone

Alchemical free energy methods have found tremendous success over the last few decades, becoming
key components of drug discovery pipelines. Despite many and ongoing innovations in this area, with
several methodological improvements published each year, it remains challenging to consistently run
free energy campaigns using state-of-the-art tools and best practices. In many cases, doing so requires
expert knowledge, and/or the use of expensive closed source software. The Open Free Energy
Consortium (https://openfree.energy/) was created with the aim of addressing these issues. A joint
effort between academic and industry partners, the consortium aims to create and maintain
reproducible and extensible open source toolkits for running large scale free energy campaigns. The
initial flagship product of the Open Free Energy Consortium is the OpenFE toolkit
(https://github.com/OpenFreeEnergy/openfe/), a permissively licensed open-source Python
framework to setup, calculate, and analyse relative binding free energies.

In this contribution we will summarise the progress and outputs of the project after its first year of
operation. First we present the first benchmark results of the OpenFE toolkit. We compare the
accuracy of ΔΔG estimates for approximately 200 ligand transformations calculated using the OpenFE
toolkit with the OpenMM molecular dynamics engine, against previously published benchmark
systems. We also assess the relative compute performance and accuracy of various equilibrium and
non-equilibrium methods, including Hamiltonian replica exchange, self-adjusted mixture sampling,
and non-equilibrium switching. Finally, we detail next steps for the toolkit, including the addition of
support for other molecular dynamics engines, absolute binding free energies, and the ongoing
curation of protein-ligand free energy benchmarks.