Machine-learned molecular mechanics force field for the simulation of protein-ligand systems and beyond

• URL: http://arxiv.org/abs/2307.07085v4
• Date: Fri, 8 Dec 2023 23:11:17 GMT
• Title: Machine-learned molecular mechanics force field for the simulation of protein-ligand systems and beyond
• Authors: Kenichiro Takaba, Iv\'an Pulido, Pavan Kumar Behara, Chapin E. Cavender, Anika J. Friedman, Michael M. Henry, Hugo MacDermott Opeskin, Christopher R. Iacovella, Arnav M. Nagle, Alexander Matthew Payne, Michael R. Shirts, David L. Mobley, John D. Chodera, Yuanqing Wang
• Abstract summary: Development of reliable and molecular mechanics (MM) force fields is indispensable for biomolecular simulation and computer-aided drug design. We introduce a generalized and machine-learned MM force field, ttexttespaloma-0.3, and an end-to-end differentiable framework using graph neural networks. The force field reproduces quantum chemical energetic properties of chemical domains highly relevant to drug discovery, including small molecules, peptides, and nucleic acids.
• Score: 33.54862439531144
• License: http://creativecommons.org/licenses/by/4.0/
• Abstract: The development of reliable and extensible molecular mechanics (MM) force fields -- fast, empirical models characterizing the potential energy surface of molecular systems -- is indispensable for biomolecular simulation and computer-aided drug design. Here, we introduce a generalized and extensible machine-learned MM force field, \texttt{espaloma-0.3}, and an end-to-end differentiable framework using graph neural networks to overcome the limitations of traditional rule-based methods. Trained in a single GPU-day to fit a large and diverse quantum chemical dataset of over 1.1M energy and force calculations, \texttt{espaloma-0.3} reproduces quantum chemical energetic properties of chemical domains highly relevant to drug discovery, including small molecules, peptides, and nucleic acids. Moreover, this force field maintains the quantum chemical energy-minimized geometries of small molecules and preserves the condensed phase properties of peptides, self-consistently parametrizing proteins and ligands to produce stable simulations leading to highly accurate predictions of binding free energies. This methodology demonstrates significant promise as a path forward for systematically building more accurate force fields that are easily extensible to new chemical domains of interest.

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