Abstract
This work elucidates structural and mechanistic properties of natural metalloenzymes and biomimetics complexes in their catalytic functioning. In these studies, a wide range of computational approaches including quantum mechanics (QM), molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) have been employed. Using a variety of structural and chemical factors such as nucleophile and substrate activation, vdW and electrostatic interactions and steric effects, we investigated mechanisms of three critical reactions, a) phosphoester and amide bond hydrolysis, b) catechol oxidation and c) carbon dioxide hydration. In particular, we derived mechanistic insights into amide and phosphoester hydrolysis by Mazur-type organophosphorus acid anhydrase (OPAA) that exhibits the unique ability to selectively cleave tertiary amide bonds and P-F bonds. We also investigated phosphoester hydrolysis and carbon dioxide hydration using do novo designed multi-active sites containing β-sheet rich peptidic aggregates. Additionally, we explored a complex interplay between non-covalent interactions in the mechanism of a heteronuclear Fe-Zn core containing complex. Furthermore, an AI- accelerated screening pipeline is developed to identify small molecules for the selective inhibition of the Spermine Synthase enzyme implicated in brain cancer. The results gleaned from these may lead to the design of efficient catalysts for many critical reactions and drug molecules for the treatment of brain cancer.