Control of thiolate nucleophilicity and specificity in zinc metalloproteins by hydrogen bonding: lessons from model compound studies.

A single hydrogen bond between an amide N-H and a thiolate sulfur in model complexes designed to mimic the binding site of zinc thiolate proteins, is shown to reduce the reactivity of the thiolate toward electrophiles by up to 2 orders of magnitude. In addition a single such bond is also sufficient to achieve nearly 100% regiospecificity of reaction between a strong, and hence inherently indiscriminate, alkylating agent like trimethyl oxonium tetrafluoroborate and a single sulfur in a dithiolate construct. The importance of these results in understanding how two systems such as the zinc fingers of the GATA family and the Escherichia coli DNA repair protein Ada which share the same pseudotetrahedral structure and tetrascysteinyl ligation around the zinc can fulfill such widely divergent (structural vs reactive) roles and how specificity of reaction in multithiolate-containing systems can be achieved is discussed.