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.

Lambda-ABF: Simplified, Portable, Accurate, and Cost-Effective Alchemical Free-Energy Computation

“…Still, these strategies are always associated with a heavy computational cost and with practical complexity, limiting their adoption by nonexpert users. The necessary steps in state-of-the-art methods include the manual or automated optimization of the lambda schedule , and a postprocessing step to obtain free-energy differences. Additionally, even in the simpler case of relative free energies, the need to sample slow orthogonal degrees of freedom such as solvent reorganization or binding site relaxation has pushed the development of dedicated techniques such as Hamiltonian replica exchange. − In this case, sampling of such degrees of freedom is improved by exchanging configurations between different lambda states.…”