title: Differential effects of the Zn-His-Bkb vs Zn-His-[Asp/Glu] triad on Zn-core stability and reactivity.
abstract: The most common partner of the Zn-bound His is the Asp/Glu carboxylate side chain in catalytic Zn sites and the backbone (Bkb) carbonyl group in structural Zn sites. To elucidate the factors governing the selection of the second-shell partner of the Zn-bound His in structural/catalytic Zn sites, systematic studies using density functional theory and continuum dielectric calculations were performed to determine the relative contributions of the second-shell Bkb carbonyl and the Asp/Glu carboxylate to the Zn-core stability and reactivity. The results show that the contributions of the second-shell Bkb carbonyl and Asp/Glu carboxylate to the Zn-core stability depend mainly on the solvent accessibility of the Zn-site and the composition of the Zn-core. They reveal the advantage of a second-shell Bkb carbonyl in anionic Zn cavities: it stabilizes anionic, buried Zn-cores more than the corresponding negatively charged Asp/Glu carboxylate, thus explaining the absence of the Zn-His-Asp/Glu triad in structural [Zn(Cys)3(His)]- cores. They also reveal the advantage of a second-shell Asp/Glu carboxylate in catalytic Zn-cores: relative to a Bkb carbonyl group, it increases (i) the HOMO energy of the cationic/neutral zinc core, (ii) the reactivity of the attacking Zn-bound OH-, (iii) electron transfer to the substrate, and (iv) the stability of the metal complex upon electron transfer. Furthermore, a second-shell Asp/Glu carboxylate could facilitate product release in the common cationic catalytic cores, by acting as a proton acceptor of the Zn-bound His creating an Asp...His- dyad that stabilizes the zinc dication more than the respective Bkb...His0 dyad.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan ROC.
authors.forename: Yen-Lin
authors.initials: YL
authors.lastname: Lin
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Lee
authors.forename: Carmay
authors.initials: C
authors.lastname: Lim
mesh_terms: D001224:Aspartic Acid / Q000737:chemistry; D020134:Catalytic Domain; D004579:Electron Transport; D004798:Enzymes / Q000737:chemistry; D018698:Glutamic Acid / Q000737:chemistry; D006639:Histidine / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008667:Metalloproteins / Q000737:chemistry*; D011487:Protein Conformation; D015032:Zinc / Q000737:chemistry*
chemical_list: D004798:Enzymes; D008024:Ligands; D008667:Metalloproteins; D001224:Aspartic Acid; D018698:Glutamic Acid; D006639:Histidine; D015032:Zinc