Intramolecular chelation of Zn2+ by α- and β-mercaptocarboxamides.: A parallel ab initio and polarizable molecular mechanics investigation. assessment of the role of multipole transferability

alpha- and beta -mercaptocarboxamides constitute the Zn2+-ligating entity of several highly potent metalloenzyme inhibitors. We have studied their interaction energies with Zn2+ 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 Zn2+-metalloenzymes with inhibitors. If the distributed multipoles and polarizabilities are those derived for each ligand in its appropriate Zn2+-binding conformation, a close reproduction of the nb 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 Zn2+ This representation accounts for the nonadditivity occurring in the Zn2+-methanethiolate-formamide complex, and justifies the use of the distributed multipoles on the fragments for the construction of larger and flexible molecules. (C) 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1038-1047, 2001.