Adaptive lambda schemes for efficient relative binding free energy calculation.

Abstract

The relative free energy perturbation (RFEP) calculation is one of the most theoretically sound computational chemistry approaches for the binding affinity prediction. However, its application is often hindered by the complexity of the calculation choices and the requirement of expertise in the field. Improper lambda scheme of RFEP may result in deviations from an accurate description of the perturbation process and is prone to erroneous affinity predictions. To address such challenges, an automated adaptive lambda method is proposed where the adaptive lambda schemes are obtained through a split-and-merge algorithm based on the pilot runs. The newly established workflow along with a series of improvements to the perturbation settings increases the consistency of the RFEP calculation results. Comparing the pilot and adaptive lambda schemes, the latter demonstrated improvements in convergence and reproducibility and lowered the mean unsigned error and the root-mean-square error. Overall, the adaptive lambda method is a reliable and robust choice to predict small molecule relative binding free energy and can be capitalized to benefit routine RFEP calculations for drug discovery projects.