Alchemical Binding Free Energy Calculations in AMBER20: Advances and Best Practices for Drug Discovery

Predicting protein–ligand
binding affinities and the associated
thermodynamics of biomolecular recognition is a primary objective
of structure-based drug design. Alchemical free energy simulations
offer a highly accurate and computationally efficient route to achieving
this goal. While the AMBER molecular dynamics package has successfully
been used for alchemical free energy simulations in academic research
groups for decades, widespread impact in industrial drug discovery
settings has been minimal because of the previous limitations within
the AMBER alchemical code, coupled with challenges in system setup
and postprocessing workflows. Through a close academia-industry collaboration
we have addressed many of the previous limitations with an aim to
improve accuracy, efficiency, and robustness of alchemical binding
free energy simulations in industrial drug discovery applications.
Here, we highlight some of the recent advances in AMBER20 with a focus
on alchemical binding free energy (BFE) calculations, which are less
computationally intensive than alternative binding free energy methods
where full binding/unbinding paths are explored. In addition to scientific
and technical advances in AMBER20, we also describe the essential
practical aspects associated with running relative alchemical BFE
calculations, along with recommendations for best practices, highlighting
the importance not only of the alchemical simulation code but also
the auxiliary functionalities and expertise required to obtain accurate
and reliable results. This work is intended to provide a contemporary
overview of the scientific, technical, and practical issues associated
with running relative BFE simulations in AMBER20, with a focus on
real-world drug discovery applications.