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Reaction Mechanism of Manganese Superoxide Dismutase Studied by Combined Quantum and Molecular Mechanical Calculations and Multiconfigurational Methods.

Srnec, Martin; Aquilante, Francesco; Ryde, Ulf LU and Rulíšek, Lubomír (2009) In The Journal of Physical Chemistry Part B 113(17). p.6074-6086
Abstract
Manganese superoxide dismutases (MnSODs) are enzymes that convert two molecules of the poisonous superoxide radical into molecular oxygen and hydrogen peroxide. During the reaction, the manganese ion cycles between the Mn(2+) and Mn(3+) oxidation states and accomplishes its enzymatic action in two half-cycles (corresponding to the oxidation and reduction of O(2)(*-)). Despite many experimental and theoretical studies dealing with SODs, including quantum chemical active-site-model studies of numerous variants of the reaction mechanisms, several details of MnSOD enzymatic action are still unclear. In this study, we have modeled and compared four reaction pathways (one associative, one dissociative, and two second-sphere) in a protein... (More)
Manganese superoxide dismutases (MnSODs) are enzymes that convert two molecules of the poisonous superoxide radical into molecular oxygen and hydrogen peroxide. During the reaction, the manganese ion cycles between the Mn(2+) and Mn(3+) oxidation states and accomplishes its enzymatic action in two half-cycles (corresponding to the oxidation and reduction of O(2)(*-)). Despite many experimental and theoretical studies dealing with SODs, including quantum chemical active-site-model studies of numerous variants of the reaction mechanisms, several details of MnSOD enzymatic action are still unclear. In this study, we have modeled and compared four reaction pathways (one associative, one dissociative, and two second-sphere) in a protein environment using the QM/MM approach (combined quantum and molecular mechanics calculations) at the density functional theory level. The results were complemented by CASSCF/CASPT2/MM single-point energy calculations for the most plausible models to account properly for the multireference character of the various spin multiplets. The results indicate that the oxidation of O(2)(*-) to O(2) most likely occurs by an associative mechanism following a two-state (quartet-octet) reaction profile. The barrier height is estimated to be less than 25 kJ.mol(-1). On the other hand, the conversion of O(2)(*-) to H(2)O(2) is likely to take place by a second-sphere mechanism, that is, without direct coordination of the superoxide radical to the manganese center. The reaction pathway involves the conical intersection of two quintet states, giving rise to an activation barrier of approximately 60 kJ.mol(-1). The calculations also indicate that the associative mechanism can represent a competitive pathway in the second half-reaction with the overall activation barrier being only slightly higher than the activation barrier in the second-sphere mechanism. The activation barriers along the proposed reaction pathways are in very good agreement with the experimentally observed reaction rates of SODs (k(cat) approximately 10(4)-10(5) s(-1)). (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
in
The Journal of Physical Chemistry Part B
volume
113
issue
17
pages
6074 - 6086
publisher
The American Chemical Society
external identifiers
  • wos:000265529900051
  • pmid:19344143
  • scopus:66349088253
ISSN
1520-5207
DOI
10.1021/jp810247u
language
English
LU publication?
yes
id
89ffed3a-a09c-4525-9fac-a832d0a2863d (old id 1392482)
date added to LUP
2009-05-12 09:18:49
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2017-01-01 05:25:00
@article{89ffed3a-a09c-4525-9fac-a832d0a2863d,
  abstract     = {Manganese superoxide dismutases (MnSODs) are enzymes that convert two molecules of the poisonous superoxide radical into molecular oxygen and hydrogen peroxide. During the reaction, the manganese ion cycles between the Mn(2+) and Mn(3+) oxidation states and accomplishes its enzymatic action in two half-cycles (corresponding to the oxidation and reduction of O(2)(*-)). Despite many experimental and theoretical studies dealing with SODs, including quantum chemical active-site-model studies of numerous variants of the reaction mechanisms, several details of MnSOD enzymatic action are still unclear. In this study, we have modeled and compared four reaction pathways (one associative, one dissociative, and two second-sphere) in a protein environment using the QM/MM approach (combined quantum and molecular mechanics calculations) at the density functional theory level. The results were complemented by CASSCF/CASPT2/MM single-point energy calculations for the most plausible models to account properly for the multireference character of the various spin multiplets. The results indicate that the oxidation of O(2)(*-) to O(2) most likely occurs by an associative mechanism following a two-state (quartet-octet) reaction profile. The barrier height is estimated to be less than 25 kJ.mol(-1). On the other hand, the conversion of O(2)(*-) to H(2)O(2) is likely to take place by a second-sphere mechanism, that is, without direct coordination of the superoxide radical to the manganese center. The reaction pathway involves the conical intersection of two quintet states, giving rise to an activation barrier of approximately 60 kJ.mol(-1). The calculations also indicate that the associative mechanism can represent a competitive pathway in the second half-reaction with the overall activation barrier being only slightly higher than the activation barrier in the second-sphere mechanism. The activation barriers along the proposed reaction pathways are in very good agreement with the experimentally observed reaction rates of SODs (k(cat) approximately 10(4)-10(5) s(-1)).},
  author       = {Srnec, Martin and Aquilante, Francesco and Ryde, Ulf and Rulíšek, Lubomír},
  issn         = {1520-5207},
  language     = {eng},
  number       = {17},
  pages        = {6074--6086},
  publisher    = {The American Chemical Society},
  series       = {The Journal of Physical Chemistry Part B},
  title        = {Reaction Mechanism of Manganese Superoxide Dismutase Studied by Combined Quantum and Molecular Mechanical Calculations and Multiconfigurational Methods.},
  url          = {http://dx.doi.org/10.1021/jp810247u},
  volume       = {113},
  year         = {2009},
}