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Capturing non-local through-bond effects when fragmenting molecules for quantum chemical torsion scans

View ORCID ProfileChaya D Stern, View ORCID ProfileChristopher I Bayly, View ORCID ProfileDaniel G A Smith, View ORCID ProfileJosh Fass, View ORCID ProfileLee-Ping Wang, View ORCID ProfileDavid L Mobley, View ORCID ProfileJohn D Chodera
doi: https://doi.org/10.1101/2020.08.27.270934
Chaya D Stern
1Tri-Insitutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA; Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065 USA · Funded by NSF GRFP DGE-1257284; MolSSI NSF ACI-1547580; NSF CHE-1738979
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Christopher I Bayly
2OpenEye Scientific Software
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Daniel G A Smith
3The Molecular Sciences Software Institute, Blacksburg, Virginia 24060 USA · Funded by NSF OAC-1547580; Open Force Field Consortium
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Josh Fass
4Tri-Insitutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA; Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065 USA · Funded by NSF CHE-1738979
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Lee-Ping Wang
5Department of Chemistry, University of California, Davis, California 95616 USA
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David L Mobley
6Departments of Pharmaceutical Sciences and Chemistry, University of California, Irvine, California 92697 · Funded by NIH R01GM132386
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John D Chodera
7Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065 USA; BIH Einstein Visiting Professor, Charité Universitätsmedizin, Berlin · Funded by NSF CHE-1738979; NIH R01GM132386; NIH P30CA008748; Sloan Kettering Institute
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  • For correspondence: john.chodera@choderalab.org
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Abstract

Accurate molecular mechanics force fields for small molecules are essential for predicting protein-ligand binding affinities in drug discovery and understanding the biophysics of biomolecular systems. Torsion potentials derived from quantum chemical (QC) calculations are critical for determining the conformational distributions of small molecules, but are computationally expensive and scale poorly with molecular size. To reduce computational cost and avoid the complications of distal through-space intramolecular interactions, molecules are generally fragmented into smaller entities to carry out QC torsion scans. However, torsion potentials, particularly for conjugated bonds, can be strongly affected by through-bond chemistry distal to the torsion itself. Poor fragmentation schemes have the potential to significantly disrupt electronic properties in the region around the torsion by removing important, distal chemistries, leading to poor representation of the parent molecule’s chemical environment and the resulting torsion energy profile. Here we show that a rapidly computable quantity, the fractional Wiberg bond order (WBO), is a sensitive reporter on whether the chemical environment around a torsion has been disrupted. We show that the WBO can be used as a surrogate to assess the robustness of fragmentation schemes and identify conjugated bond sets. We use this concept to construct a validation set by exhaustively fragmenting a set of druglike organic molecules and examine their corresponding WBO distributions derived from accessible conformations that can be used to evaluate fragmentation schemes. To illustrate the utility of the WBO in assessing fragmentation schemes that preserve the chemical environment, we propose a new fragmentation scheme that uses rapidly-computable AM1 WBOs, which are available essentially for free as part of standard AM1-BCC partial charge assignment. This approach can simultaneously maximize the chemical equivalency of the fragment and the substructure in the larger molecule while minimizing fragment size to accelerate QC torsion potential computation for small molecules and reducing undesired through-space steric interactions.

Competing Interest Statement

JDC was a member of the Scientific Advisory Board for Schrodinger, LLC during part of this study. JDC and DLM is a current member of the Scientific Advisory Board of OpenEye Scientific Software. DLM is an Open Science Fellow with Silicon Therapeutics. 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, 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.

Footnotes

  • https://github.com/openforcefield/fragmenter

  • https://github.com/choderalab/fragmenter_data

  • https://github.com/openforcefield/qca-dataset-submission

  • https://doi.org/gg8w5d

Copyright 
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 August 28, 2020.
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Capturing non-local through-bond effects when fragmenting molecules for quantum chemical torsion scans
Chaya D Stern, Christopher I Bayly, Daniel G A Smith, Josh Fass, Lee-Ping Wang, David L Mobley, John D Chodera
bioRxiv 2020.08.27.270934; doi: https://doi.org/10.1101/2020.08.27.270934
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Capturing non-local through-bond effects when fragmenting molecules for quantum chemical torsion scans
Chaya D Stern, Christopher I Bayly, Daniel G A Smith, Josh Fass, Lee-Ping Wang, David L Mobley, John D Chodera
bioRxiv 2020.08.27.270934; doi: https://doi.org/10.1101/2020.08.27.270934

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