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Factors Governing When a Metal-Bound Water is Deprotonated in Proteins

Abstract

Understanding when a metal-bound water molecule in a protein is deprotonated is important as this affects the charge distribution in the metal-binding/enzyme active site and thus their interactions, enzyme mechanism, as well as inhibitor design. The protonation state of the metal-bound water molecule at a given pH depends on its pKa value, which in turn depends on the properties of the cation, its ligands, and the protein environment. Here, we reveal how and the extent to which (i) the first-shell composition (type, charge, number of ligands), (ii) the metal site’s immediate surroundings (first-shellsecond-shell hydrogen-bonding interactions, metal–ligand distance constraints, and ligand-binding mode) and (iii) the protein architecture and coupled solvent interactions (long-range electrostatic interactions and solvent exposure of the site) affect the Zn2+-bound water pKa. The results, which are consistent with available experimental pKa values of Zn2+-bound water, provide guidelines to predict when the Zn2+-bound water would be likely deprotonated at physiological pH.

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Publication details

The article was received on 27 Jul 2018, accepted on 05 Nov 2018 and first published on 05 Nov 2018


Article type: Paper
DOI: 10.1039/C8CP04776F
Citation: Phys. Chem. Chem. Phys., 2018, Accepted Manuscript
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    Factors Governing When a Metal-Bound Water is Deprotonated in Proteins

    C. Grauffel and C. Lim, Phys. Chem. Chem. Phys., 2018, Accepted Manuscript , DOI: 10.1039/C8CP04776F

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