HessFit: A Toolkit to Derive Automated Force Fields from Quantum Mechanical Information

In this study, we introduce a novel approach to enhance the accuracy of molecular dynamics simulations by refining the force fields (FFs) through a combination of transferable parameters and molecule-specific characteristics derived from quantum mechanical (QM) calculations. Traditional FFs often prioritize generality over precision, leading to limitations in the accuracy of accurately capturing intra- and intermolecular interactions. To address this, we present an open-source toolkit, called HessFit, designed to integrate QM-derived bonded parameters and atomic charges into existing FFs. In combination with bond, angle, torsional, and nonbonded parameters derivation, HessFit can easily extract multiple barrier terms of dihedrals from QM Hessian and gradient or return all terms through a fitting procedure scheme of QM potential energy surface. We showcase the effectiveness of HessFit through comprehensive evaluations of vibrational properties across a diverse set of small molecules and demonstrate that experimental results support its ability in predicting thermodynamic properties of organic molecules compared to previous state-of-the-art approaches. We further explore its application to Zn²⁺ metalloprotein models, which are hard systems to treat with automatic approaches. Our results demonstrate that HessFit parameters compete with GAFF2 and OPLS parameters to describing small organic molecules, and its feasibility is also comparable to current FFs used to modeling nonstandard residues in Zn proteins for molecular dynamics simulations. The effectiveness of the HessFit protocol makes it a valuable tool for deriving or extending force field parameters for novel compounds in several molecular modeling applications.