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Protonation States of Homocitrate and Nearby Residues in Nitrogenase Studied by Computational Methods and Quantum Refinement

Cao, Lili LU ; Caldararu, Octav LU and Ryde, Ulf LU (2017) In Journal of Physical Chemistry B 121(35). p.8242-8262
Abstract

Nitrogenase is the only enzyme that can break the triple bond in N2 to form two molecules of ammonia. The enzyme has been thoroughly studied with both experimental and computational methods, but there is still no consensus regarding the atomic details of the reaction mechanism. In the most common form, the active site is a MoFe7S9C(homocitrate) cluster. The homocitrate ligand contains one alcohol and three carboxylate groups. In water solution, the triply deprotonated form dominates, but because the alcohol (and one of the carboxylate groups) coordinate to the Mo ion, this may change in the enzyme. We have performed a series of computational calculations with molecular dynamics (MD), quantum mechanical... (More)

Nitrogenase is the only enzyme that can break the triple bond in N2 to form two molecules of ammonia. The enzyme has been thoroughly studied with both experimental and computational methods, but there is still no consensus regarding the atomic details of the reaction mechanism. In the most common form, the active site is a MoFe7S9C(homocitrate) cluster. The homocitrate ligand contains one alcohol and three carboxylate groups. In water solution, the triply deprotonated form dominates, but because the alcohol (and one of the carboxylate groups) coordinate to the Mo ion, this may change in the enzyme. We have performed a series of computational calculations with molecular dynamics (MD), quantum mechanical (QM) cluster, combined QM and molecular mechanics (QM/MM), QM/MM with Poisson-Boltzmann and surface area solvation, QM/MM thermodynamic cycle perturbations, and quantum refinement methods to settle the most probable protonation state of the homocitrate ligand in nitrogenase. The results quite conclusively point out a triply deprotonated form (net charge -3) with a proton shared between the alcohol and one of the carboxylate groups as the most stable at pH 7. Moreover, we have studied eight ionizable protein residues close to the active site with MD simulations and determined the most likely protonation states.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Physical Chemistry B
volume
121
issue
35
pages
21 pages
publisher
The American Chemical Society
external identifiers
  • scopus:85029079821
  • wos:000410597700002
ISSN
1520-6106
DOI
10.1021/acs.jpcb.7b02714
language
English
LU publication?
yes
id
f1f8a23b-2b37-4c14-b2be-bac8a547d158
date added to LUP
2017-09-26 09:54:23
date last changed
2018-05-20 04:37:29
@article{f1f8a23b-2b37-4c14-b2be-bac8a547d158,
  abstract     = {<p>Nitrogenase is the only enzyme that can break the triple bond in N<sub>2</sub> to form two molecules of ammonia. The enzyme has been thoroughly studied with both experimental and computational methods, but there is still no consensus regarding the atomic details of the reaction mechanism. In the most common form, the active site is a MoFe<sub>7</sub>S<sub>9</sub>C(homocitrate) cluster. The homocitrate ligand contains one alcohol and three carboxylate groups. In water solution, the triply deprotonated form dominates, but because the alcohol (and one of the carboxylate groups) coordinate to the Mo ion, this may change in the enzyme. We have performed a series of computational calculations with molecular dynamics (MD), quantum mechanical (QM) cluster, combined QM and molecular mechanics (QM/MM), QM/MM with Poisson-Boltzmann and surface area solvation, QM/MM thermodynamic cycle perturbations, and quantum refinement methods to settle the most probable protonation state of the homocitrate ligand in nitrogenase. The results quite conclusively point out a triply deprotonated form (net charge -3) with a proton shared between the alcohol and one of the carboxylate groups as the most stable at pH 7. Moreover, we have studied eight ionizable protein residues close to the active site with MD simulations and determined the most likely protonation states.</p>},
  author       = {Cao, Lili and Caldararu, Octav and Ryde, Ulf},
  issn         = {1520-6106},
  language     = {eng},
  month        = {09},
  number       = {35},
  pages        = {8242--8262},
  publisher    = {The American Chemical Society},
  series       = {Journal of Physical Chemistry B},
  title        = {Protonation States of Homocitrate and Nearby Residues in Nitrogenase Studied by Computational Methods and Quantum Refinement},
  url          = {http://dx.doi.org/10.1021/acs.jpcb.7b02714},
  volume       = {121},
  year         = {2017},
}