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Title: Computational Investigation of the Interplay of Substrate Positioning and Reactivity in Catechol O-Methyltransferase

Abstract

Catechol O-methyltransferase (COMT) is a SAM- and Mg2+-dependent methyltransferase that regulates neurotransmitters through methylation. Simulations and experiments have identified divergent catecholamine substrate orientations in the COMT active site: molecular dynamics simulations have favored a monodentate coordination of catecholate substrates to the active site Mg2+, and crystal structures instead preserve bidentate coordination along with short (2.65 Å) methyl donor-acceptor distances. We carry out longer dynamics (up to 350 ns) to quantify interconversion between bidentate and monodentate binding poses. We provide a systematic determination of the relative free energy of the monodentate and bidentate structures in order to identify whether structural differences alter the nature of the methyl transfer mechanism and source of enzymatic rate enhancement. We demonstrate that the bidentate and monodentate binding modes are close in energy but separated by a 7 kcal/mol free energy barrier. Analysis of interactions in the two binding modes reveals that the driving force for monodentate catecholate orientations in classical molecular dynamics simulations is derived from stronger electrostatic stabilization afforded by alternate Mg2+ and surrounding ligands is permitted. SQM/MM free energy barriers for methyl transfer from bidentate and monodentate catecholate configurations are comparable at around 21–22 kcal/mol, in good agreement with experiment (18–19 kcal/mol). Overall,more » the work suggests that both binding poses are viable for methyl transfer, and accurate descriptions of charge transfer and electrostatics are needed to provide balanced relative barriers when multiple binding poses are accessible, for example in other transferases.« less

Authors:
 [1];  [1]; ORCiD logo [1];  [2]
  1. Massachusetts Institute of Technology, Cambridge, Massachusetts, (United States). Department of Chemical Engineering
  2. Universidade Nova de Lisboa Instituto de Tecnologia Quimica e Biologica (Portugal)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Science Foundation (NSF)
OSTI Identifier:
1627802
Grant/Contract Number:  
AC02-06CH11357; ACI-1053575
Resource Type:
Accepted Manuscript
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Volume: 11; Journal Issue: 8; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
Science & Technology - Other Topics; Free energy; Crystal structure; Oxygen; Molecular dynamics; Hydrogen bonding; Electrostatic bonding; Anions; Catecholamines

Citation Formats

Patra, Niladri, Ioannidis, Efthymios I., Kulik, Heather J., and Soares, Claudio M. Computational Investigation of the Interplay of Substrate Positioning and Reactivity in Catechol O-Methyltransferase. United States: N. p., 2016. Web. doi:10.1371/journal.pone.0161868.
Patra, Niladri, Ioannidis, Efthymios I., Kulik, Heather J., & Soares, Claudio M. Computational Investigation of the Interplay of Substrate Positioning and Reactivity in Catechol O-Methyltransferase. United States. doi:10.1371/journal.pone.0161868.
Patra, Niladri, Ioannidis, Efthymios I., Kulik, Heather J., and Soares, Claudio M. Fri . "Computational Investigation of the Interplay of Substrate Positioning and Reactivity in Catechol O-Methyltransferase". United States. doi:10.1371/journal.pone.0161868. https://www.osti.gov/servlets/purl/1627802.
@article{osti_1627802,
title = {Computational Investigation of the Interplay of Substrate Positioning and Reactivity in Catechol O-Methyltransferase},
author = {Patra, Niladri and Ioannidis, Efthymios I. and Kulik, Heather J. and Soares, Claudio M.},
abstractNote = {Catechol O-methyltransferase (COMT) is a SAM- and Mg2+-dependent methyltransferase that regulates neurotransmitters through methylation. Simulations and experiments have identified divergent catecholamine substrate orientations in the COMT active site: molecular dynamics simulations have favored a monodentate coordination of catecholate substrates to the active site Mg2+, and crystal structures instead preserve bidentate coordination along with short (2.65 Å) methyl donor-acceptor distances. We carry out longer dynamics (up to 350 ns) to quantify interconversion between bidentate and monodentate binding poses. We provide a systematic determination of the relative free energy of the monodentate and bidentate structures in order to identify whether structural differences alter the nature of the methyl transfer mechanism and source of enzymatic rate enhancement. We demonstrate that the bidentate and monodentate binding modes are close in energy but separated by a 7 kcal/mol free energy barrier. Analysis of interactions in the two binding modes reveals that the driving force for monodentate catecholate orientations in classical molecular dynamics simulations is derived from stronger electrostatic stabilization afforded by alternate Mg2+ and surrounding ligands is permitted. SQM/MM free energy barriers for methyl transfer from bidentate and monodentate catecholate configurations are comparable at around 21–22 kcal/mol, in good agreement with experiment (18–19 kcal/mol). Overall, the work suggests that both binding poses are viable for methyl transfer, and accurate descriptions of charge transfer and electrostatics are needed to provide balanced relative barriers when multiple binding poses are accessible, for example in other transferases.},
doi = {10.1371/journal.pone.0161868},
journal = {PLoS ONE},
number = 8,
volume = 11,
place = {United States},
year = {2016},
month = {8}
}

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