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Optimized CGenFF force-field parameters for acylphosphate and N-phosphonosulfonimidoyl functional groups

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Abstract

We report an optimized set of CGenFF parameters that can be used to model small molecules containing acylphosphate and N-phosphonosulfonimidoyl functional groups in combination with the CHARMM force field. Standard CGenFF procedures were followed to obtain bonded interaction parameters, which were validated by geometry optimizations, comparison to the results of calculations at the MP2/6-31+G(d) level of theory, and molecular dynamics simulations. In addition, partial atomic charges were assigned so that the energy of hydrogen bonding of the model compounds with water was correctly reproduced. The availability of these parameters will facilitate computational studies of enzymes that generate acyladenylate intermediates during catalytic turnover. In addition, given that the N-phosphonosulfonimidoyl moiety is a stable transition state analog for the reaction of ammonia with an acyladenylate, the parameters developed in this study should find use in efforts to develop novel and potent inhibitors of various glutamine-dependent amidotransferases that have been validated as drug targets. Topology and parameter files for the model compounds used in this study, which can be combined with other CGenFF parameters in computational studies of more complicated acylphosphates and N-phosphonosulfonimidates are made available.

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Acknowledgments

The authors wish to thank Alex D. MacKerell, Jr., and Kenno Vanommeslaeghe (Maryland) for helpful discussions. Computational resources for this work were provided by the University of Florida High Performance Computing Center. Funding for this work was obtained from the National Institutes of Health (DK061666) and Indiana University Purdue University Indianapolis.

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Authors and Affiliations

  1. Department of Chemistry, University of Florida, Gainesville, FL, 32611, USA

    Lamees Hegazy

  2. Department of Chemistry & Chemical Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN, 46202, USA

    Nigel G. J. Richards

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  1. Lamees Hegazy
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  2. Nigel G. J. Richards
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Correspondence to Nigel G. J. Richards.

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ESM 1

The calculated QM and MM vibrational spectra together with simulation trajectory data for the N-phosphonosulfonimidoyl derivative 5, and full topology and parameter information for the model compounds (4 and 5) employed in this study, is provided as Supplementary material. (PDF 413 kb)

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Hegazy, L., Richards, N.G.J. Optimized CGenFF force-field parameters for acylphosphate and N-phosphonosulfonimidoyl functional groups. J Mol Model 19, 5075–5087 (2013). https://doi.org/10.1007/s00894-013-1990-x

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  • DOI: https://doi.org/10.1007/s00894-013-1990-x

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