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QM/MM Study of the Conversion of Oxophlorin into Verdoheme by Heme Oxygenase

Alavi, Fatemeh Sadat; Zahedi, Mansour; Safari, Nasser and Ryde, Ulf LU (2017) In Journal of Physical Chemistry B 121(51). p.11427-11436
Abstract

Heme oxygenase is an enzyme that degrades heme, thereby recycling iron in most organisms, including humans. Pervious density functional theory (DFT) calculations have suggested that iron(III) hydroxyheme, an intermediate generated in the first step of heme degradation by heme oxygenase, is converted to iron(III) superoxo oxophlorin in the presence of dioxygen. In this article, we have studied the detailed mechanism of conversion of iron(III) superoxo oxophlorin to verdoheme by using combined quantum mechanics and molecular mechanics (QM/MM) calculations. The calculations employed the B3LYP method and the def2-QZVP basis set, considering dispersion effects with the DFT-D3 approach, obtaining accurate energies with large QM regions of... (More)

Heme oxygenase is an enzyme that degrades heme, thereby recycling iron in most organisms, including humans. Pervious density functional theory (DFT) calculations have suggested that iron(III) hydroxyheme, an intermediate generated in the first step of heme degradation by heme oxygenase, is converted to iron(III) superoxo oxophlorin in the presence of dioxygen. In this article, we have studied the detailed mechanism of conversion of iron(III) superoxo oxophlorin to verdoheme by using combined quantum mechanics and molecular mechanics (QM/MM) calculations. The calculations employed the B3LYP method and the def2-QZVP basis set, considering dispersion effects with the DFT-D3 approach, obtaining accurate energies with large QM regions of almost 1000 atoms. The reaction was found to be exothermic by -35 kcal/mol, with a rate-determining barrier of 19 kcal/mol in the doublet state. The protein environment and especially water in the enzyme pocket significantly affects the reaction by decreasing the reaction activation energies and changing the structures by providing strategic hydrogen bonds.

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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
51
pages
10 pages
publisher
The American Chemical Society
external identifiers
  • scopus:85040107215
ISSN
1520-6106
DOI
10.1021/acs.jpcb.7b08332
language
English
LU publication?
yes
id
20ef0f74-1b98-482f-b0eb-53cb441dfa31
date added to LUP
2018-01-15 10:19:19
date last changed
2018-07-08 04:29:32
@article{20ef0f74-1b98-482f-b0eb-53cb441dfa31,
  abstract     = {<p>Heme oxygenase is an enzyme that degrades heme, thereby recycling iron in most organisms, including humans. Pervious density functional theory (DFT) calculations have suggested that iron(III) hydroxyheme, an intermediate generated in the first step of heme degradation by heme oxygenase, is converted to iron(III) superoxo oxophlorin in the presence of dioxygen. In this article, we have studied the detailed mechanism of conversion of iron(III) superoxo oxophlorin to verdoheme by using combined quantum mechanics and molecular mechanics (QM/MM) calculations. The calculations employed the B3LYP method and the def2-QZVP basis set, considering dispersion effects with the DFT-D3 approach, obtaining accurate energies with large QM regions of almost 1000 atoms. The reaction was found to be exothermic by -35 kcal/mol, with a rate-determining barrier of 19 kcal/mol in the doublet state. The protein environment and especially water in the enzyme pocket significantly affects the reaction by decreasing the reaction activation energies and changing the structures by providing strategic hydrogen bonds.</p>},
  author       = {Alavi, Fatemeh Sadat and Zahedi, Mansour and Safari, Nasser and Ryde, Ulf},
  issn         = {1520-6106},
  language     = {eng},
  month        = {12},
  number       = {51},
  pages        = {11427--11436},
  publisher    = {The American Chemical Society},
  series       = {Journal of Physical Chemistry B},
  title        = {QM/MM Study of the Conversion of Oxophlorin into Verdoheme by Heme Oxygenase},
  url          = {http://dx.doi.org/10.1021/acs.jpcb.7b08332},
  volume       = {121},
  year         = {2017},
}