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

19 April 2021, Version 2
This content is a preprint and has not undergone peer review at the time of posting.


The quantum mechanical bespoke (QUBE) force field approach has been developed to facilitate the automated derivation of potential energy function parameters for modelling 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 GPU acceleration will facilitate high-throughput alchemical free energy calculations.


Quantum mechanics
Force fields
Molecular mechanics
Free Energy Calculations
protein-ligand binding
molecular dynamics

Supplementary materials



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