QM/MM study of the reaction mechanism of sulfite oxidase
Caldararu, Octav LU ; Feldt, Milica ; Cioloboc, Daniela ; Van Severen, Marie Céline LU ; Starke, Kerstin LU ; Mata, Ricardo A. ; Nordlander, Ebbe LU and Ryde, Ulf LU
(2018)
In Scientific Reports
8(1).
- Abstract
Sulfite oxidase is a mononuclear molybdenum enzyme that oxidises sulfite to sulfate in many organisms, including man. Three different reaction mechanisms have been suggested, based on experimental and computational studies. Here, we study all three with combined quantum mechanical (QM) and molecular mechanical (QM/MM) methods, including calculations with large basis sets, very large QM regions (803 atoms) and QM/MM free-energy perturbations. Our results show that the enzyme is set up to follow a mechanism in which the sulfur atom of the sulfite substrate reacts directly with the equatorial oxo ligand of the Mo ion, forming a Mo-bound sulfate product, which dissociates in the second step. The first step is rate limiting, with a barrier... (More)
Sulfite oxidase is a mononuclear molybdenum enzyme that oxidises sulfite to sulfate in many organisms, including man. Three different reaction mechanisms have been suggested, based on experimental and computational studies. Here, we study all three with combined quantum mechanical (QM) and molecular mechanical (QM/MM) methods, including calculations with large basis sets, very large QM regions (803 atoms) and QM/MM free-energy perturbations. Our results show that the enzyme is set up to follow a mechanism in which the sulfur atom of the sulfite substrate reacts directly with the equatorial oxo ligand of the Mo ion, forming a Mo-bound sulfate product, which dissociates in the second step. The first step is rate limiting, with a barrier of 39-49 kJ/mol. The low barrier is obtained by an intricate hydrogen-bond network around the substrate, which is preserved during the reaction. This network favours the deprotonated substrate and disfavours the other two reaction mechanisms. We have studied the reaction with both an oxidised and a reduced form of the molybdopterin ligand and quantum-refinement calculations indicate that it is in the normal reduced tetrahydro form in this protein.
(Less)
- author
- Caldararu, Octav
LU
; Feldt, Milica
; Cioloboc, Daniela
; Van Severen, Marie Céline
LU
; Starke, Kerstin
LU
; Mata, Ricardo A.
; Nordlander, Ebbe
LU
and Ryde, Ulf
LU
- organization
- publishing date
- 2018-12-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Scientific Reports
- volume
- 8
- issue
- 1
- article number
- 4684
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:29549261
- scopus:85044206019
- ISSN
- 2045-2322
- DOI
- 10.1038/s41598-018-22751-6
- language
- English
- LU publication?
- yes
- id
- 7e77d999-7309-45b6-adcd-7c2275fb93f5
- date added to LUP
- 2018-04-03 12:13:42
- date last changed
- 2024-03-18 07:30:30
@article{7e77d999-7309-45b6-adcd-7c2275fb93f5,
abstract = {{<p>Sulfite oxidase is a mononuclear molybdenum enzyme that oxidises sulfite to sulfate in many organisms, including man. Three different reaction mechanisms have been suggested, based on experimental and computational studies. Here, we study all three with combined quantum mechanical (QM) and molecular mechanical (QM/MM) methods, including calculations with large basis sets, very large QM regions (803 atoms) and QM/MM free-energy perturbations. Our results show that the enzyme is set up to follow a mechanism in which the sulfur atom of the sulfite substrate reacts directly with the equatorial oxo ligand of the Mo ion, forming a Mo-bound sulfate product, which dissociates in the second step. The first step is rate limiting, with a barrier of 39-49 kJ/mol. The low barrier is obtained by an intricate hydrogen-bond network around the substrate, which is preserved during the reaction. This network favours the deprotonated substrate and disfavours the other two reaction mechanisms. We have studied the reaction with both an oxidised and a reduced form of the molybdopterin ligand and quantum-refinement calculations indicate that it is in the normal reduced tetrahydro form in this protein.</p>}},
author = {{Caldararu, Octav and Feldt, Milica and Cioloboc, Daniela and Van Severen, Marie Céline and Starke, Kerstin and Mata, Ricardo A. and Nordlander, Ebbe and Ryde, Ulf}},
issn = {{2045-2322}},
language = {{eng}},
month = {{12}},
number = {{1}},
publisher = {{Nature Publishing Group}},
series = {{Scientific Reports}},
title = {{QM/MM study of the reaction mechanism of sulfite oxidase}},
url = {{http://dx.doi.org/10.1038/s41598-018-22751-6}},
doi = {{10.1038/s41598-018-22751-6}},
volume = {{8}},
year = {{2018}},
}