The selective hydrolysis of the extremely stable peptide (-(O=)C-NH-) and phosphoester ((O=)(RO)(RO)(P-O-R)) bonds of molecules by metallohydrolases is required in a wide range of biological, biotechnological and industrial applications. They include cell death, DNA repair, protein engineering, genomics, therapeutics and bioremediation of pesticides and nerve agents. Both these bonds are extremely stable and the half-life for the hydrolysis of peptide and phosphoester bonds is 350-600 and ~10<sup>7</sup> years, respectively, at room temperature and pH = 4-8. We are deriving guiding principles of these fundamental reactions for the development of efficient bio-inspired synthetic metallohydrolases. These analogues are likely to offer the following advantages over natural enzymes: (1) inexpensive and recyclable, (2) smaller in size with little or no steric constraints, and (3) tunable for specific functions. In a multi-step strategy, we are obtaining insights concerning the roles of metals and ligands in the functioning of natural and synthetic metallohydrolases to design more efficient variants of the latter. In the first step, we have investigated the roles of metal ions, ligands and second coordination shell residues in the catalytic functioning of novel enzymes such as mononuclear metal center containing insulin degrading enzyme (IDE) and neprelysin (NEP) and binuclear core containing <i>Streptomyces griseus </i>aminopeptidase (SgAP) and glycerophosphodiesterase (GpdQ). In the next step, the knowledge regarding the mechanisms of existing synthetic analogues (Co(II), Fe(II), Cu(II), Zn(II), and Zr(IV) metal complexes) of IDE, NEP, SgAP and GpdQ is combined with the information acquired in the previous step to design more efficient synthetic metallohydrolases through modifications in the metal(s) and ligand environment. In these studies, several state-of-the-art theoretical and computational chemistry techniques involving molecular dynamics, quantum mechanics and hybrid quantum mechanics/molecular mechanics are integrated with experiments.

Development of bio-inspired synthetic metallohydrolases

2019 Spring National Meeting

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