Factors Governing the Protonation State of Zn-Bound Histidine in Proteins: A DFT/CDM Study
- 6 February 2004
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 126 (8) , 2602-2612
- https://doi.org/10.1021/ja038827r
Abstract
We have performed systematic theoretical studies to elucidate the factors governing the His protonation/deprotonation state in Zn-binding sites, especially those containing the ubiquitous Zn-His-Asp/Glu triad. Specifically, we have addressed the following three questions: (1) How does the transfer of the Zn-bound His imidazole proton to the second-shell Asp/Glu carboxylate oxygen depend on the composition of the other first-shell ligands and the solvent accessibility of the metal-binding site? (2) Can any second-shell ligand with a proton acceptor group such as the backbone carbonyl oxygen also act as a proton acceptor? (3) What is the effect of the Asp/Glu in the Zn-His-Asp/Glu triad on the Zn-bound water protonation state? To address these questions, we used a combination of quantum mechanical and continuum dielectric methods to compute the free energies for deprotonating a Zn-bound imidazole/water in various Zn complexes. The calculations show that whether the Zn-bound His is protonated or deprotonated depends on (1) the solvent accessibility of the metal-binding site, and (2) the Lewis acid ability of Zn, which is indirectly determined by both the first- and the second-shell Zn ligands. The calculations also show that the effect of the Zn-His-Asp/Glu interaction on the nucleophilicity of the Zn-bound water depends on the solvent accessibility of the catalytic Zn site. Furthermore, they show that the Asp/Glu side chain in the Zn-His-Asp/Glu triad can increase the negative charge of its partner, His, and create an anionic hole that may stabilize a cation in buried cavities, provided that the Zn complex is cationic/neutral. The findings of this work are in accord with available experimental data.This publication has 66 references indexed in Scilit:
- Functional Characterization of Human Carbonic Anhydrase II Variants with Altered Zinc Binding SitesBiochemistry, 1994
- Engineering a cysteine ligand into the zinc binding site of human carbonic anhydrase IIBiochemistry, 1993
- Zine Complexes of Cysteine, Histidine, and Derivatives Thereof: Potentiometric determination of their compositions and stabilitiesHelvetica Chimica Acta, 1993
- Structure of native and apo carbonic anhydrase II and structure of some of its anion-ligand complexesJournal of Molecular Biology, 1992
- Ionization potentials and electron affinities in aqueous solutionJournal of the American Chemical Society, 1986
- Synthesis and structural systematics of ethane-1,2-dithiolato complexesInorganic Chemistry, 1986
- CHARMM: A program for macromolecular energy, minimization, and dynamics calculationsJournal of Computational Chemistry, 1983
- Proton Transfer in the Catalytic Mechanism of Carbonic AnhydraseCritical Reviews in Biochemistry, 1983
- A molecular orbital study on the zinc-water-Glu 270 system in carboxypeptidase A.CHEMICAL & PHARMACEUTICAL BULLETIN, 1981
- Similarities in active center geometries of zinc-containing enzymes, proteases and dehydrogenasesJournal of Molecular Biology, 1978