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CysxHisyZn2+ interactions: Thiol vs. thiolate coordination

CysxHisyZn2+ interactions: Thiol vs. thiolate coordination In zinc proteins, the Zn2+ cation frequently binds with a tetrahedral coordination to cysteine and histidine side chains, for example, in many DNA‐binding proteins, where it plays primarily a structural role. We examine the possibility of thiolate protonation in CysxHisyZn2+ groups, both in proteins and in solution, through a combination of theoretical calculations and database analysis. Seventy‐five percent of the thiolate‐coordinated zincs in the Cambridge Structural Database are tetrahedral, while di‐alkanethiol coordination always involves five or more ligands. Ab initio quantum calculations are performed on (ethanethiol/thiolate)3imidazole‐Zn2+ complexes in vacuum, yielding geometries and gas phase basicities. Protonating one (respectively two) thiolates increases the Zn‐S(thiol) distance by 0.4 Å (respectively 0.3 Å), providing a structural marker for protonation. The stabilities of the complexes in solution are compared by combining the gas phase basicities with continuum dielectric solvation calculations. In a continuum solvent with permittivity ε = 4, 20, or 80, one of three thiolates is predicted to be protonated at neutral pH. By extension, Cys4Zn2+ groups are expected to be protonated in the same conditions. In contrast, most Cys3His and Cys4 geometries in the Protein Data Bank (PDB) appear consistent with all‐thiolate Zn2+ coordination. This apparent discrepancy is resolved by two recent surveys of zinc protein structures, which suggest that these all‐thiolate sites are stabilized by charged and polar groups nearby in the protein, thus overcoming their intrinsic instability. However, the experimental resolution is not sufficient in all the PDB structures to rule out a thiol/thiolate mixture, and protonated thiolates may occur in some proteins not solved at high resolution or not represented in the PDB, as suggested by recent mass spectrometry experiments; this possibility should be allowed for in X‐ray structure refinement. Proteins 2002;49:37–48. © 2002 Wiley‐Liss, Inc. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Proteins: Structure Function and Bioinformatics Wiley

CysxHisyZn2+ interactions: Thiol vs. thiolate coordination

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References (75)

Publisher
Wiley
Copyright
Copyright © 2002 Wiley Subscription Services
ISSN
0887-3585
eISSN
1097-0134
DOI
10.1002/prot.10200
pmid
12211014
Publisher site
See Article on Publisher Site

Abstract

In zinc proteins, the Zn2+ cation frequently binds with a tetrahedral coordination to cysteine and histidine side chains, for example, in many DNA‐binding proteins, where it plays primarily a structural role. We examine the possibility of thiolate protonation in CysxHisyZn2+ groups, both in proteins and in solution, through a combination of theoretical calculations and database analysis. Seventy‐five percent of the thiolate‐coordinated zincs in the Cambridge Structural Database are tetrahedral, while di‐alkanethiol coordination always involves five or more ligands. Ab initio quantum calculations are performed on (ethanethiol/thiolate)3imidazole‐Zn2+ complexes in vacuum, yielding geometries and gas phase basicities. Protonating one (respectively two) thiolates increases the Zn‐S(thiol) distance by 0.4 Å (respectively 0.3 Å), providing a structural marker for protonation. The stabilities of the complexes in solution are compared by combining the gas phase basicities with continuum dielectric solvation calculations. In a continuum solvent with permittivity ε = 4, 20, or 80, one of three thiolates is predicted to be protonated at neutral pH. By extension, Cys4Zn2+ groups are expected to be protonated in the same conditions. In contrast, most Cys3His and Cys4 geometries in the Protein Data Bank (PDB) appear consistent with all‐thiolate Zn2+ coordination. This apparent discrepancy is resolved by two recent surveys of zinc protein structures, which suggest that these all‐thiolate sites are stabilized by charged and polar groups nearby in the protein, thus overcoming their intrinsic instability. However, the experimental resolution is not sufficient in all the PDB structures to rule out a thiol/thiolate mixture, and protonated thiolates may occur in some proteins not solved at high resolution or not represented in the PDB, as suggested by recent mass spectrometry experiments; this possibility should be allowed for in X‐ray structure refinement. Proteins 2002;49:37–48. © 2002 Wiley‐Liss, Inc.

Journal

Proteins: Structure Function and BioinformaticsWiley

Published: Jan 1, 2002

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