H-Bonding Interactions and Control of Thiolate Nucleophilicity and Specificity in Model Complexes of Zinc Metalloproteins

It is shown in model complexes designed to mimic the binding site of zinc-thiolate proteins that a single hydrogen
bond between an amide N−H and a Zn-coordinated thiolate reduces its reactivity toward electrophiles by up to 2
orders of magnitude. In addition, we show that a single N−H···S hydrogen bond is sufficient to achieve near 100%
regiospecificity of reaction between a strong, and hence inherently indiscriminate, alkylating agent like trimethyloxonium
tetraflouroborate and a single sulfur in a dithiolate construct. The importance of these results in understanding how
systems such as the zinc fingers of the GATA family and the E. coli DNA repair protein Ada, which share the same
pseudotetrahedral structure and tetracysteinyl ligation around the zinc, can fulfill such widely divergent (structural
vs reactive) roles and how specificity of reaction in such multi-thiolate containing systems can be achieved is
discussed.