15: Exploring the effects of hydrogen bonding on the reactivity in synthetic suicidal ZnII DNA N-Ada20 repair protein analogs

Abstract: Through millions of years of evolution, nature has designed its own DNA defense mechanisms in the form of chemosensors. Chemosensors are a variety of repair proteins designed to protect cells from the toxic effects of mutagenic chemicals and radiation by directly cleaving methylated tags from various parts of DNA. Interestingly, many repair proteins involve ZnII to restore DNA and prevent degradation and mutagenic effects. One intriguing metalloprotein of interest is the suicidal DNA Adaptive (N-Ada20) repair protein, which repairs methyl-phosphotriester backbone damage via self-methylation. The exact mechanism behind the self-methylation process remains unknown, but two pathways have been proposed: a dissociative pathway that involves the formation of a zinc-thiolate ionic pair, and an associative pathway that involves a four-membered ringed sigma-metathesis transition state. Former research has revealed that thiolate dissociation is dependent on the primary coordination sphere of the metalloprotein's active site. However, we hypothesize that secondary coordination sphere hydrogen bonding effects within our complexes also support the dissociative mechanism. To test this hypothesis, a series of substituted zinc-thiolate complexes of the form [(L)Zn-SPh-X]+ were synthesized, where the ligand (L) is tris(2-pyridylmethyl)amine containing a pendant hydrogen bond donor group. Kinetic experiments with the alkylating reagent CH3I were performed using 1H NMR and a Hammett plot was constructed to examine the relationship between the electronic effect of thiolate substituents on the mechanism of thiolate alkylation.