Topology Automated Force-Field Interactions (TAFFI): A Framework for Developing Transferable Force Fields

Abstract

Force-field development has undergone a revolution in the past decade with the proliferation of quantum chemistry based parametrizations and the introduction of machine learning approximations of the atomistic potential energy surface. Nevertheless, transferable force fields with broad coverage of organic chemical space remain necessary for applications in materials and chemical discovery where throughput, consistency, and computational cost are paramount. Here, we introduce a force-field development framework called Topology Automated Force-Field Interactions (TAFFI) for developing transferable force fields of varying complexity against an extensible database of quantum chemistry calculations. TAFFI formalizes the concept of atom typing and makes it the basis for generating systematic training data that maintains a one-to-one correspondence with force-field terms. This feature makes TAFFI arbitrarily extensible to new chemistries while maintaining internal consistency and transferability. As a demonstration of TAFFI, we have developed a fixed-charge force-field, TAFFI-gen, from scratch that includes coverage for common organic functional groups that is comparable to established transferable force fields. The performance of TAFFI-gen was benchmarked against OPLS and GAFF for reproducing several experimental properties of 87 organic liquids. The consistent performance of these force fields, despite their distinct origins, validates the TAFFI framework while also providing evidence of the representability limitations of fixed-charge force fields.

Comprehensive exploration of graphically defined reaction spaces

“…Here a depth of one was used, meaning that the bond types are unique out to their immediate bonded neighbors. This is analogous to prior definitions of models compounds for generating force-fields 24 and parameterizing increment theories. 25 The model reaction is formed by truncating the parent reaction at the specified graphical depth, then hydrogenating the structure to a level that preserves the hybridization of the reacting atoms in the reactant and product.…”

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

“…By retaining common MM functional forms, the potentials may readily be implemented in widely used MM software and used in, for example, free energy calculations. Bespoke intramolecular bond, angle and, particularly, torsion parameters may be readily derived from a small number of QM calculations either by fitting to Hessian matrices [18][19][20][21] or potential energy surface scans 22,23 . Atom-centred partial charges can be routinely derived from either semi-empirical calculations 24,25 , or QM electrostatic potential fitting 26,27 , or atoms-in-molecule electron density partitioning [28][29][30][31] .…”

“…Bespoke intramolecular bond, angle and, particularly, torsion parameters may be readily derived from a small number of QM calculations either by fitting to Hessian matrices [18][19][20][21] or potential energy surface scans. 22,23 Atom-centred partial charges can be routinely derived from either semi-empirical calculations, 24,25 or QM electrostatic potential fitting, 26,27 or atomsin-molecule electron density partitioning. [28][29][30][31] Less common, but perhaps most interestingly, is the possibility of using atoms-in-molecule electron density partitioning to derive other components of the non-bonded interaction from QM, in particular dispersion coefficients (C 6 , [32][33][34][35] C 8 , 36,37 .…”

Open Force Field BespokeFit: Automating Bespoke Torsion Parametrization at Scale

“…Such an approach to transferable FF design is often successful as evidenced by numerous retrospective − and prospective , studies, which show good agreement between experiment and simulation. Critical applications of FFs include alchemical free energy calculations, which have become a widespread, relatively low-cost computational tool to aid the identification and development of high-binding-affinity small molecules in the early stages of drug discovery campaigns .…”