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

Abstract

The quantum mechanical bespoke (QUBE) forcefield 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 nonnucleoside 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.

Evaluating the use of absolute binding free energy in the fragment optimisation process

“…For example, recent work by Khalak et al 30 demonstrates that non-equilibrium absolute binding free energy can be used to bridge differences between large conformational differences between bound and unbound states. The use of higher quality force fields, especially via bespoke ligand parameterisations 63 , 64 , may also be key to alleviating some of the accuracy limitations identified here. We hope that future work will focus on improving both the precision and accuracy of ABFE results for fragment optimisation.…”

Efficient Crystal Structure Prediction for Structurally Related Molecules with Accurate and Transferable Tailor-Made Force Fields

“…In addition, it opens the opportunity for CSP components to be leveraged for computer-guided molecule design in advance of molecular synthesis to make accurate yet computationally affordable predictions of physicochemical properties, including solubility, permeability, and potency. 30 , 33 , 58 …”

“…This ability to employ an accurate TMFF that exhibits transferability within structurally related molecules represents a paradigm shift in computing crystal energy landscapes with unprecedented efficiency and accuracy. In addition, it opens the opportunity for CSP components to be leveraged for computer-guided molecule design in advance of molecular synthesis to make accurate yet computationally affordable predictions of physicochemical properties, including solubility, permeability, and potency. ,, …”

Exploration and validation of force field design protocols through QM-to-MM mapping

“…Once all other parameters are in place, flexible torsion parameters can be fit to QM dihedral scans using interfaces between QUBEKit and external QM and MM software packages 34 . A small number of mapping parameters (in this case free atom radii for use in the derivation of Lennard-Jones parameters) is used to ensure accuracy of condensed phase properties 34 , and the resulting force fields have also been shown to perform well in the calculation of protein-ligand binding free energies [45][46][47] .…”

“…34 A small number of mapping parameters (in this case free atom radii for use in the derivation of Lennard-Jones parameters) is used to ensure accuracy of condensed phase properties, 34 and the resulting force fields have also been shown to perform well in the calculation of protein-ligand binding free energies. [45][46][47] Force field design choices can be tested and optimised…”