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A consistent S-Adenosylmethionine force field improved by dynamic Hirshfeld-I atomic charges for biomolecular simulation

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Abstract

S-Adenosylmethionine (AdoMet) is involved in many biological processes as cofactor in enzymes transferring its sulfonium methyl group to various substrates. Additionally, it is used as drug and nutritional supplement to reduce the pain in osteoarthritis and against depression. Due to the biological relevance of AdoMet it has been part of various computational simulation studies and will also be in the future. However, to our knowledge no rigorous force field parameter development for its simulation in biological systems has been reported. Here, we use electronic structure calculations combined with molecular dynamics simulations in explicit solvent to develop force field parameters compatible with the AMBER99 force field. Additionally, we propose new dynamic Hirshfeld-I atomic charges which are derived from the polarized electron density of AdoMet in aqueous solution to describe its electrostatic interactions in biological systems. The validation of the force field parameters and the atomic charges is performed against experimental interproton NOE distances of AdoMet in aqueous solution and crystal structures of AdoMet in the cavity of three representative proteins.

Graphical Abstract

A S-Adenosylmethionine force field was developed together with Dynamic Hirshfeld-I charges (shown color coded in figure) and validated against various experimental data.

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Acknowledgments

EVM is thankful for funding support provided by FONDECYT 11121179 and Grant ICM No 120082. DS thanks CONICYT for the graduate scholarship 21130517.

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Authors and Affiliations

  1. Departamento de Físico Química, Facultad de Ciencias Químicas, Universidad de Concepción, Milenium Nucleus Chemical Processes and Catalysis, Concepción, Chile

    David Adrian Saez & Esteban Vöhringer-Martinez

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  1. David Adrian Saez
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  2. Esteban Vöhringer-Martinez
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Correspondence to Esteban Vöhringer-Martinez.

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Saez, D.A., Vöhringer-Martinez, E. A consistent S-Adenosylmethionine force field improved by dynamic Hirshfeld-I atomic charges for biomolecular simulation. J Comput Aided Mol Des 29, 951–961 (2015). https://doi.org/10.1007/s10822-015-9864-1

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  • DOI: https://doi.org/10.1007/s10822-015-9864-1

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