Implementation of the QUBE Force Field in SOMD for High-Throughput Alchemical Free-Energy Calculations

The quantum mechanical bespoke (QUBE) force-field approach has been developed to facilitate the automated derivation of potential energy function parameters for modeling protein-ligand binding. To date, the approach has been validated in the context of Monte Carlo simulations of protein-ligand complexes. We describe here the implementation of the QUBE force field in the alchemical free-energy calculation molecular dynamics simulation package SOMD. The implementation is validated by demonstrating the reproducibility of absolute hydration free energies computed with the QUBE force field across the SOMD and GROMACS software packages. We further demonstrate, by way of a case study involving two series of non-nucleoside inhibitors of HIV-1 reverse transcriptase, that the availability of QUBE in a modern simulation package that makes efficient use of graphics processing unit acceleration will facilitate high-throughput alchemical free-energy calculations.

Automated summary

The QUBE force-field approach has been developed for deriving potential energy function parameters for modeling protein-ligand binding, validated in Monte Carlo simulations, and successfully implemented in the SOMD and GROMACS software packages. It is shown that the availability of QUBE in a modern simulation package that utilizes GPU acceleration will facilitate high-throughput alchemical free-energy calculations.