Intramolecular chelation of Zn 2+ by α‐ and β‐mercaptocarboxamides. A parallel ab initio and polarizable molecular mechanics investigation. Assessment of the role of multipole transferability

α‐ and β‐mercaptocarboxamides constitute the Zn 2+ ‐ligating entity of several highly potent metalloenzyme inhibitors. We have studied their interaction energies with Zn 2+ using the polarizable molecular mechanics procedure SIBFA, and compared them to the corresponding ab initio supermolecule ones. Such validations are necessary to subsequently undertake simulations on complexes of Zn 2+ –metalloenzymes with inhibitors. If the distributed multipoles and polarizabilities are those derived for each ligand in its appropriate Zn 2+ ‐binding conformation, a close reproduction of the ab initio binding energies is afforded. However, this representation is not tractable upon increasing the size of the ligands and/or to explore a continuum of binding conformations. This makes it necessary to construct the ligands by resorting to a library of constitutive fragments, namely in this case methanethiolate, formamide, and methane covalently connected together. A close reproduction of the ab initio interaction energies is enabled, but only if the ligand–ligand interactions are computed simultaneously with those occurring with Zn 2+ . This representation accounts for the nonadditivity occurring in the Zn 2+ –methanethiolate–formamide complex, and justifies the use of the distributed multipoles on the fragments for the construction of larger and flexible molecules. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1038–1047, 2001