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

✍ Scribed by Gilles Tiraboschi; Marie-Claude Fournié-Zaluski; Bernard-Pierre Roques; Nohad Gresh

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: English
• Weight: 379 KB
• Volume: 22
• Category: Article
• ISSN: 0192-8651
• DOI: 10.1002/jcc.1064

✦ Synopsis

Abstract

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