The design of efficient synthetic analogues of metalloenzymes is a formidable task. It is not surprising that in comparison to natural enzymes the reactions promoted by a vast majority of existing analogues are substantially slower, exhibit lower selectivity and occur with lower catalytic turnover. This could be due to the following reasons: (1) the ligand environment of these analogues does not match the chemical properties of amino acid residues of enzyme active sites, (2) the metal centers of these analogues contain 1-3 more ligands than the metal centers of enzymes, (3) they lack hydrogen bonding networks of enzymes, and (4) the absence of second coordination shell residues of enzymes in these analogues that provide significant rate enhancements and selectivity. The design of such analogues with improved activities requires a deeper understanding of the functioning of both natural and synthetic enzymes and chemical modifications in the latter on the basis of that insight.<br/> <br/>We have employed a plethora of computational approaches such as molecular dynamics (MD), quantum mechanics (QM), and hybrid quantum mechanics/molecular mechanics (QM/MM) to derive this understanding. In particular, we have systematically studied the effects of the ligand environment, metal ion(s), second coordination shell residues, and hydrogen bonding networks on the mechanisms and energetics of a variety of mono- and binuclear metal center containing enzymes such as insulin degrading enzyme (IDE), neprilysin (NEP), <i>Streptomyces griseus </i>aminopeptidase (SgAP) and glycerophosphodiesterase (GpdQ) and their metal (Co(II), Fe(II), Cu(II), Zn(II), and Zr(IV)) containing synthetic analogues. These results have elucidated individual contributions made by distinct chemical factors in the enormous rate-accelerations provided by these enzymes. Additionally, they have provided interesting insights into designing metal complexes to catalyze the hydrolysis of amide, phosphoesters, nitriles and other reactions including epoxide opening, aldol condensation, Michael addition, and Diels-Alder reaction.

Insights into the design of synthetic analogues of metalloenzymes

2019 Spring National Meeting

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