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Escaping atom types in force fields using direct chemical perception David L Mobley, Caitlin Colleen Bannan, Andrea Rizzi, Christopher I. Bayly, John Damon Chodera, Victoria T Lim, Nathan M. Lim, Kyle A. Beauchamp, David R Slochower, Michael R. Shirts, and Peter Kenneth Eastman J. Chem. Theory Comput., Just Accepted Manuscript • DOI: 10.1021/acs.jctc.8b00640 • Publication Date (Web): 11 Oct 2018 Downloaded from http://pubs.acs.org on October 11, 2018
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Journal of Chemical Theory and Computation Preprint ahead of submission — August 31, 2018
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Escaping atom types in force fields using direct chemical perception David L. Mobley1,2 , Caitlin C. Bannan2 , Andrea Rizzi3,5 , Christopher I. Bayly4 , John D. Chodera5 , Victoria T. Lim2 , Nathan M. Lim1 , Kyle A. Beauchamp6 , David R. Slochower7 , Michael R. Shirts8 , Michael K. Gilson7 , Peter K. Eastman9 1 Department
of Pharmaceutical Science, University of California, Irvine CA 92697; 2 Department of Chemistry, University of California, Irvine CA 92697; 3 Tri-Institutional Program in Computational Biology and Medicine, New York NY 10065; 4 OpenEye Scientific Software, Santa Fe NM 87507; 5 Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York NY 10065; 6 Counsyl, South San Francisco, CA 94080; 7 Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego; 8 Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO 80309; 9 Department of Chemistry, Stanford University, Stanford, CA 94305 *For correspondence:
[email protected] (DLM) Abstract
Traditional approaches to specifying a molecular mechanics force field encode all the information needed to assign force field parameters to a given molecule into a discrete set of atom types. This is equivalent to a representation consisting of a molecular graph comprising a set of vertices, which represent atoms labeled by atom type, and unlabeled edges, which represent chemical bonds. Bond stretch, angle bend, and dihedral parameters are then assigned by looking up bonded pairs, triplets, and quartets of atom types in parameter tables to assign valence terms, and using the atom types themselves to assign nonbonded parameters. This approach, which we call indirect chemical perception because it operates on the intermediate graph of atom-typed nodes, creates a number of technical problems. For example, atom types must be sufficiently complex to encode all necessary information about the molecular environment, making it difficult to extend force fields encoded this way. Atom typing also results in a proliferation of redundant parameters applied to chemically equivalent classes of valence terms, needlessly increasing force field complexity. Here, we describe a new approach to assigning force field parameters terms direct chemical perception that avoids these problems, called the SMIRKS Native Open Force Field (SMIRNOFF) format. Rather than working through the intermediary of the atomtyped graph, direct chemical perception operates directly on the unmodified chemical graph of the molecule to assign parameters. In particular, parameters are assigned to each type of force field term—e.g., bond stretch, angle bend, torsion, and Lennard-Jones—based on standard chemical substructure queries implemented via the industry-standard SMARTS chemical perception language, using SMIRKS extensions that permit labeling of specific atoms within a chemical pattern. We demonstrate the power and generality of this approach using examples of specific molecules that pose problems for indirect chemical perception, and construct and validate a minimalist yet very general force field, SMIRNOFF99Frosst. We find that a parameter definition file only ∼300 lines long provides coverage of all but
