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Proton transfer at metal sites in proteins studied by quantum mechanical free-energy perturbations

Kaukonen, Markus LU ; Söderhjelm, Pär LU ; Heimdal, Jimmy LU and Ryde, Ulf LU (2008) In Journal of Chemical Theory and Computation 4(6). p.985-1001
Abstract
Catalytic metal sites in enzymes frequently have second-sphere carboxylate groups that neutralize the charge of the site and share protons with first-sphere ligands. This gives rise to an ambiguity concerning the position of this proton, which has turned out to be hard to settle with experimental, as well as theoretical, methods. We study three such proton-transfer reactions in two proteins and show that, in [Ni,Fe] hydrogenase, the bridging Cys-546 ligand is deprotonated by His-79, whereas in oxidized copper nitrite reductase, the His-100 ligand is neutral and the copper-bound water molecule is deprotonated by Asp-98. We show that these reactions strongly depend on the electrostatic interactions with the surrounding protein and solvent,... (More)
Catalytic metal sites in enzymes frequently have second-sphere carboxylate groups that neutralize the charge of the site and share protons with first-sphere ligands. This gives rise to an ambiguity concerning the position of this proton, which has turned out to be hard to settle with experimental, as well as theoretical, methods. We study three such proton-transfer reactions in two proteins and show that, in [Ni,Fe] hydrogenase, the bridging Cys-546 ligand is deprotonated by His-79, whereas in oxidized copper nitrite reductase, the His-100 ligand is neutral and the copper-bound water molecule is deprotonated by Asp-98. We show that these reactions strongly depend on the electrostatic interactions with the surrounding protein and solvent, because there is a large change in the dipole moment of the active site (2-6 D). Neither vacuum quantum mechanical (QM) calculations with large models, a continuum solvent, or a Poisson-Boltzmann treatment of the surroundings, nor combined QM and molecular mechanics (QM/MM) optimizations give reliable estimates of the proton-transfer energies (mean absolute deviations of over 20 kJ/mol). Instead, QM/MM free-energy perturbations are needed to obtain reliable estimates of the reaction energies. These calculations also indicate what interactions and residues are important for the energy, showing how the quantum system may be systematically enlarged. With such a procedure, results with an uncertainty of similar to 10 kJ/mol can be obtained, provided that a proper QM method is used. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Chemical Theory and Computation
volume
4
issue
6
pages
985 - 1001
publisher
The American Chemical Society
external identifiers
  • wos:000256640700013
  • scopus:54249102103
ISSN
1549-9618
DOI
10.1021/ct700347h
language
English
LU publication?
yes
id
193e611d-0125-48ab-8d28-9c8c3197501f (old id 1191381)
date added to LUP
2008-09-08 14:39:53
date last changed
2017-03-26 03:37:43
@article{193e611d-0125-48ab-8d28-9c8c3197501f,
  abstract     = {Catalytic metal sites in enzymes frequently have second-sphere carboxylate groups that neutralize the charge of the site and share protons with first-sphere ligands. This gives rise to an ambiguity concerning the position of this proton, which has turned out to be hard to settle with experimental, as well as theoretical, methods. We study three such proton-transfer reactions in two proteins and show that, in [Ni,Fe] hydrogenase, the bridging Cys-546 ligand is deprotonated by His-79, whereas in oxidized copper nitrite reductase, the His-100 ligand is neutral and the copper-bound water molecule is deprotonated by Asp-98. We show that these reactions strongly depend on the electrostatic interactions with the surrounding protein and solvent, because there is a large change in the dipole moment of the active site (2-6 D). Neither vacuum quantum mechanical (QM) calculations with large models, a continuum solvent, or a Poisson-Boltzmann treatment of the surroundings, nor combined QM and molecular mechanics (QM/MM) optimizations give reliable estimates of the proton-transfer energies (mean absolute deviations of over 20 kJ/mol). Instead, QM/MM free-energy perturbations are needed to obtain reliable estimates of the reaction energies. These calculations also indicate what interactions and residues are important for the energy, showing how the quantum system may be systematically enlarged. With such a procedure, results with an uncertainty of similar to 10 kJ/mol can be obtained, provided that a proper QM method is used.},
  author       = {Kaukonen, Markus and Söderhjelm, Pär and Heimdal, Jimmy and Ryde, Ulf},
  issn         = {1549-9618},
  language     = {eng},
  number       = {6},
  pages        = {985--1001},
  publisher    = {The American Chemical Society},
  series       = {Journal of Chemical Theory and Computation},
  title        = {Proton transfer at metal sites in proteins studied by quantum mechanical free-energy perturbations},
  url          = {http://dx.doi.org/10.1021/ct700347h},
  volume       = {4},
  year         = {2008},
}