Abstract
In the present thesis, the structural and mechanistic information of natural and artificial metallopeptidases and aggregation mechanisms of amyloid beta (Aβ) peptide associated with Alzheimer’s disease (AD) have been explored using innovative computational techniques including quantum mechanics (QM), hybrid quantum mechanics/molecular mechanics (QM/MM ONIOM) and molecular dynamics (MD) simulations. Specifically, the mechanisms of peptide bond hydrolysis utilized by the natural mono- (insulin degrading enzyme, IDE) and binuclear (Leucine aminopeptidase, LeuAP) zinc center containing metallopeptidases have been studied. In light of many experimental efforts devoted to the designing of synthetic analogues of these enzymes, the activities of mono- and binuclear metal complexes have also been examined at the atomic level. In addition, the dimerization process of the Aβ peptide has been investigated using MD simulations which elucidated the role of key structural regions in amyloid aggregation. The results from these studies will advance scientific efforts to develop more efficient catalysts and design small molecules for the therapeutic interventions of AD.