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Capturing non-local through-bond effects in molecular mechanics force fields: II. Using fractional bond orders to fit torsion parameters

View ORCID ProfileChaya D. Stern, View ORCID ProfileJessica Maat, View ORCID ProfileDavid L. Dotson, View ORCID ProfileChristopher I. Bayly, View ORCID ProfileDaniel G. A. Smith, View ORCID ProfileDavid L. Mobley, View ORCID ProfileJohn D. Chodera
doi: https://doi.org/10.1101/2022.01.17.476653
Chaya D. Stern
1Tri-Institutional PhD Program in Chemical Biology, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065
2Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065
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Jessica Maat
3Departments of Pharmaceutical Sciences and Chemistry, University of California, Irvine, California 92697
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David L. Dotson
6The Open Force Field Consortium, Phoenix, Arizona 85003 USA
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Christopher I. Bayly
4OpenEye Scientific Software
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Daniel G. A. Smith
5The Molecular Sciences Software Institute, Blacksburg, Virginia 24060 USA
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David L. Mobley
3Departments of Pharmaceutical Sciences and Chemistry, University of California, Irvine, California 92697
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  • For correspondence: dmobley@uci.edu john.chodera@choderalab.org
John D. Chodera
2Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065
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  • For correspondence: dmobley@uci.edu john.chodera@choderalab.org
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Abstract

Accurate small molecule force fields are crucial for predicting thermodynamic and kinetic properties of drug-like molecules in biomolecular systems. Torsion parameters, in particular, are essential for determining conformational distribution of molecules. However, they are usually fit to computationally expensive quantum chemical torsion scans and generalize poorly to different chemical environments. Torsion parameters should ideally capture local through-space non-bonded interactions such as 1-4 steric and electrostatics and non-local through-bond effects such as conjugation and hyperconjugation. Non-local through-bond effects are sensitive to remote substituents and are a contributing factor to torsion parameters poor transferability. Here we show that fractional bond orders such as the Wiberg Bond Order (WBO) are sensitive to remote substituents and correctly captures extent of conjugation and hyperconjugation. We show that the relationship between WBO and torsion barrier heights are linear and can therefore serve as a surrogate to QC torsion barriers, and to interpolate torsion force constants. Using this approach we can reduce the number of computationally expensive QC torsion scans needed while maintaining accurate torsion parameters. We demonstrate this approach to a set of substituted benzene rings.

Competing Interest Statement

DLM is a current member of the Scientific Advisory Board of OpenEye Scientific Software. DLM is an Open Science Fellow with Silicon Therapeutics. JDC is a current member of the Scientific Advisory Board of OpenEye Scientific Software, Redesign Science, and Interline Therapeutics, and holds equity interests in Redesign Science and Interline Therapeutics; he was a member of the Schrodinger Scientific Advisory Board during part of this work. The Chodera laboratory receives or has received funding from multiple sources, including the National Institutes of Health, the National Science Foundation, the Parker Institute for Cancer Immunotherapy, Relay Therapeutics, Entasis Therapeutics, Silicon Therapeutics, EMD Serono (Merck KGaA), AstraZeneca, Vir Biotechnology, Bayer, XtalPi, Foresite Laboratories, the Molecular Sciences Software Institute, the Starr Cancer Consortium, the Open Force Field Consortium, Cycle for Survival, a Louis V. Gerstner Young Investigator Award, and the Sloan Kettering Institute. A complete funding history for the Chodera lab can be found at http://choderalab.org/funding

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 18, 2022.
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Capturing non-local through-bond effects in molecular mechanics force fields: II. Using fractional bond orders to fit torsion parameters
Chaya D. Stern, Jessica Maat, David L. Dotson, Christopher I. Bayly, Daniel G. A. Smith, David L. Mobley, John D. Chodera
bioRxiv 2022.01.17.476653; doi: https://doi.org/10.1101/2022.01.17.476653
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Capturing non-local through-bond effects in molecular mechanics force fields: II. Using fractional bond orders to fit torsion parameters
Chaya D. Stern, Jessica Maat, David L. Dotson, Christopher I. Bayly, Daniel G. A. Smith, David L. Mobley, John D. Chodera
bioRxiv 2022.01.17.476653; doi: https://doi.org/10.1101/2022.01.17.476653

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