OpenFE: Towards reproducible open-source alchemical free energy calculations

Over the years, alchemical free energy simulation methods have become increasingly popular and successful, often accurately predicting experimentally derived affinities up to the limit of force field accuracy. However, despite decades of work in the area, the field generally fails to meet suitable standards of reproducibility and replicability due to various ecosystem issues. These include; difficult alchemical system setup procedures, poor interoperability between simulation engines, competing simulation frameworks, and a lack of consistent validation of methods. The Open Free Energy Consortium was founded as a joint academic and industrial partnership to address these issues, focusing primarily on the development and maintenance of key open source software components to enable robust, accessible, and reproducible free energy calculations.
Here we present the newly created OpenFE toolkit (https://github.com/OpenFreeEnergy/openfe), an open-source Python library which offers a transparent and modular API to setup, orchestrate, run, and analyze large scale alchemical free energy calculations. We detail core object structures and data processing components which are used to create, represent, and store alchemical transformation networks while remaining agnost of the molecular dynamics engine. From these alchemical networks, engine and method specific solvers are applied to calculate and analyze free energy differences. We demonstrate these OpenFE toolkit components within the context of a workflow to easily set up and calculate relative binding free energies using the OpenMM molecular dynamics engine. Built with extensibility in mind, we also show how user developed components can be created, for example adding support for new ligand atom mapping tools. Finally we discuss ongoing work and future plans towards expanding the OpenFE toolkit, adding support for more MD engines and alchemical methods.