Open Force Field BespokeFit: Automating Bespoke Torsion Parametrization at Scale

Abstract

The development of accurate transferable force fields is key to realizing the full potential of atomistic modeling in the study of biological processes such as protein–ligand binding for drug discovery. State-of-the-art transferable force fields, such as those produced by the Open Force Field Initiative, use modern software engineering and automation techniques to yield accuracy improvements. However, force field torsion parameters, which must account for many stereoelectronic and steric effects, are considered to be less transferable than other force field parameters and are therefore often targets for bespoke parametrization. Here, we present the Open Force Field QCSubmit and BespokeFit software packages that, when combined, facilitate the fitting of torsion parameters to quantum mechanical reference data at scale. We demonstrate the use of QCSubmit for simplifying the process of creating and archiving large numbers of quantum chemical calculations, by generating a dataset of 671 torsion scans for druglike fragments. We use BespokeFit to derive individual torsion parameters for each of these molecules, thereby reducing the root-mean-square error in the potential energy surface from 1.1 kcal/mol, using the original transferable force field, to 0.4 kcal/mol using the bespoke version. Furthermore, we employ the bespoke force fields to compute the relative binding free energies of a congeneric series of inhibitors of the TYK2 protein, and demonstrate further improvements in accuracy, compared to the base force field (MUE reduced from 0.560.39 0.77 to 0.420.28 0.59 kcal/mol and R 2 correlation improved from 0.720.35 0.87 to 0.930.84 0.97).

Collaborative Assessment of Molecular Geometries and Energies from the Open Force Field

“…Future OpenFF updates are planned to include improved treatment of torsions (e.g., via Wiberg bond order-based parameter interpolation, which was recently implemented in the OpenFF Toolkit), off-site charges, and better handling of trivalent nitrogen geometries which we anticipate will boost performance further. Additionally, a tool for fitting bespoke torsion parameters for specific molecules/chemistries of interest is now available, likely further improving accuracy. In parallel, a biopolymer force field and an OpenFF software stack that will enable the conversion from OpenMM objects to file formats understood by other molecular simulation engines, like AMBER and GROMACS (OpenFF Interchange), will soon be released.…”

Development and Benchmarking of Open Force Field 2.0.0 — the Sage Small Molecule Force Field

“…• ForceBalance: A versatile package for force field optimization [61][62][63] • GeomeTRIC: Geometry optimizer for molecular structures with translation-rotation-internal coordinate (TRIC) system 64 • Nonbonded: Automated workflow for the optimization and assessment of the non-bonded interaction parameters of force fields against physical property datasets 65 • OpenFF-Toolkit: Chemistry toolkit for working with SMIRNOFF format force fields, as well as interface to various cheminformatics back-ends (RDKit 66 and OpenEye 67 ), and molecular dynamics engines (OpenMM) 68 • OpenFF-QCSubmit: Dataset building, validation, and data retrieval from QCArchive 69 • OpenFF-Evaluator: Automated and highly scalable physical property evaluator 70 • OpenFF-BespokeFit: Processing QCArchive data and creating ForceBalance inputs 69 • OpenMM: High performance molecular dynamics package with a variety of enhanced sampling methods 71 • PMX: Toolkit for free-energy calculation setup/analysis and biomolecular structure handling 72 • Psi4: Highly parallel electronic structure code covering a large range of methods, density functional/basis set combinations, and property evaluations 73 • QCEngine: A common Python interface to various Quantum Chemistry packages 74 • QCFractal: Server for facilitating Quantum Chemistry calculations on large compute clusters and archiving the results in a database Hydrogen attached to trivalent carbon attached to two electronegative atoms…”

Development and Benchmarking of Open Force Field 2.0.0 — the Sage Small Molecule Force Field

“…68 • OpenFF-QCSubmit: Dataset building, validation, and data retrieval from QCArchive. 69 • OpenFF-Evaluator: Automated and highly scalable physical property evaluator. 70 • OpenFF-BespokeFit: Processing QCArchive data and creating ForceBalance inputs.…”

“…70 • OpenFF-BespokeFit: Processing QCArchive data and creating ForceBalance inputs. 69 • OpenMM: High performance molecular dynamics package with a variety of enhanced sampling methods. 71 • PMX: Toolkit for free-energy calculation setup/analysis and biomolecular structure handling.…”

“…All the OpenFF-generated QM datasets reside on MolSSI's QCArchive public data repository and are accessible via its Python API (QCPortal) or by using OpenFF-QCSubmit. 69 The Sage release github repository (https://github.com/openforcefield/openff-sage) has Python scripts for dataset download, and processing the downloaded records, using the OpenFF-QCSubmit package. OpenFF Gen 2 Torsion Set 6 supplemental 2 (22 1D scans)…”