Studies of CA and model compounds indicate that hydrophobic interactions affect zinc-water pKa. The magnitude of this effect will be measured in carefully designed model compounds. A model complex designed to reproduce the hydrogen bonding network with Thr-199 and Glu-106 in human carbonic anhydrase II (CAII) will be prepared. The effect of hydrogen bonding on the pKa of zinc-coordinated water and that of the carboxylate will be quantified. A proposed carboxypeptidase enzyme mimic should bind a Zn2+ ion in a fashion stereoelectron -ically similar to that of the enzyme, involving coordination by the syn-lone pair of a carboxylate moiety. The effect of syn- vs. anti-carboxylate lone pairs on zinc-water activation will be measured. Binding studies using analogs of known enzyme inhibitors will provide metal coordination energies in the absence of other active site interactions. Finally, the synthesis and studies of future generation ligands that model Glu-270 will be undertaken. For each of these studies, synthetic organic chemistry methods are used to prepare model compounds. All new compounds are characterized by mass spectrometry.
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