Differential Effects of the Zn His Bkb vs Zn His [Asp/Glu] Triad on Zn-Core Stability and Reactivity

摘要

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 cationiceutral 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...His~0 dyad.