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Molecular dynamics simulations of alcohol dehydrogenase with a four‐ or five‐coordinate catalytic zinc ion

Ryde, Ulf LU (1995) In Proteins: Structure, Function and Genetics 21(1). p.40-56
Abstract

A detailed parameterization is presented of a zinc ion with one histidine and two cysteinate ligands, together with one or two water, hydroxide, aldehyde, alcohol, or alkoxide ligands. The parameterization is tailored for the active site of alcohol dehydrogenase and is obtained entirely from quantum chemical computations. The force‐field reproduces excellently the geometry of quantum chemically optimized zinc complexes as well as the crystallographic geometry of the active site of alcohol dehydrogenase and small organic structures. The parameterization is used in molecular dynamics simulations and molecular mechanical energy minimizations of alcohol dehydrogenase with a four‐ or five‐coordinate catalytic zinc ion. The active‐site zinc... (More)

A detailed parameterization is presented of a zinc ion with one histidine and two cysteinate ligands, together with one or two water, hydroxide, aldehyde, alcohol, or alkoxide ligands. The parameterization is tailored for the active site of alcohol dehydrogenase and is obtained entirely from quantum chemical computations. The force‐field reproduces excellently the geometry of quantum chemically optimized zinc complexes as well as the crystallographic geometry of the active site of alcohol dehydrogenase and small organic structures. The parameterization is used in molecular dynamics simulations and molecular mechanical energy minimizations of alcohol dehydrogenase with a four‐ or five‐coordinate catalytic zinc ion. The active‐site zinc ion seems to prefer four‐coordination over five‐coordination by at least 36 kJ/mol. The only stable binding site of a fifth ligand at the active‐site zinc ion is opposite to the normal substrate site, in a narrow cavity behind the zinc ion. Only molecules of the size of water or smaller may occupy this site. There are large fluctuations in the geometry of the zinc coordination sphere. A four‐coordinate water molecule alternates frequently (every 7 ps) between the substrate site and the fifth binding site and even two five coordinate water molecules may interchange ligation sites without prior dissociation. Ligand exchange at the zinc ion probably proceeds by a dissociative mechanism. The results show that it is essential to allow for bond stretching degrees of freedom in molecular dynamics simulations to get a correct description of the dynamics of the metal coordination sphere; bond length constraints may restrict the accessible part of the phase space and therefore lead to qualitatively erroneous results. © 1995 Wiley‐Liss, Inc. Copyright © 1995 Wiley‐Liss, Inc.

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author
organization
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type
Contribution to journal
publication status
published
subject
keywords
bond length constraint, effective force‐field, five‐coordination, four‐coordination, ligand dynamics, ligand exchange, reaction mechanism, zinc parameterization
in
Proteins: Structure, Function and Genetics
volume
21
issue
1
pages
17 pages
publisher
John Wiley & Sons
external identifiers
  • scopus:0028815118
ISSN
0887-3585
DOI
10.1002/prot.340210106
language
English
LU publication?
no
id
d32ecbaf-5490-4fb1-b612-c316f55715a9
date added to LUP
2017-02-04 11:30:50
date last changed
2017-08-06 05:17:11
@article{d32ecbaf-5490-4fb1-b612-c316f55715a9,
  abstract     = {<p>A detailed parameterization is presented of a zinc ion with one histidine and two cysteinate ligands, together with one or two water, hydroxide, aldehyde, alcohol, or alkoxide ligands. The parameterization is tailored for the active site of alcohol dehydrogenase and is obtained entirely from quantum chemical computations. The force‐field reproduces excellently the geometry of quantum chemically optimized zinc complexes as well as the crystallographic geometry of the active site of alcohol dehydrogenase and small organic structures. The parameterization is used in molecular dynamics simulations and molecular mechanical energy minimizations of alcohol dehydrogenase with a four‐ or five‐coordinate catalytic zinc ion. The active‐site zinc ion seems to prefer four‐coordination over five‐coordination by at least 36 kJ/mol. The only stable binding site of a fifth ligand at the active‐site zinc ion is opposite to the normal substrate site, in a narrow cavity behind the zinc ion. Only molecules of the size of water or smaller may occupy this site. There are large fluctuations in the geometry of the zinc coordination sphere. A four‐coordinate water molecule alternates frequently (every 7 ps) between the substrate site and the fifth binding site and even two five coordinate water molecules may interchange ligation sites without prior dissociation. Ligand exchange at the zinc ion probably proceeds by a dissociative mechanism. The results show that it is essential to allow for bond stretching degrees of freedom in molecular dynamics simulations to get a correct description of the dynamics of the metal coordination sphere; bond length constraints may restrict the accessible part of the phase space and therefore lead to qualitatively erroneous results. © 1995 Wiley‐Liss, Inc. Copyright © 1995 Wiley‐Liss, Inc.</p>},
  author       = {Ryde, Ulf},
  issn         = {0887-3585},
  keyword      = {bond length constraint,effective force‐field,five‐coordination,four‐coordination,ligand dynamics,ligand exchange,reaction mechanism,zinc parameterization},
  language     = {eng},
  number       = {1},
  pages        = {40--56},
  publisher    = {John Wiley & Sons},
  series       = {Proteins: Structure, Function and Genetics},
  title        = {Molecular dynamics simulations of alcohol dehydrogenase with a four‐ or five‐coordinate catalytic zinc ion},
  url          = {http://dx.doi.org/10.1002/prot.340210106},
  volume       = {21},
  year         = {1995},
}