Abstract
In this dissertation, computational chemistry techniques including quantum mechanics (QM), molecular dynamics (MD), and hybrid quantum mechanics/molecular mechanics (QM/MM) simulations were employed to derive the structural and mechanistic information of functioning of natural metalloenzymes and their synthetic analogues. In particular, the promiscuous hydrolytic activity of the natural proteins SgAP and Clavanin A were studied using a plethora of computation and experimental techniques. The chemical and structural properties of two synthetic analogues of natural hydrolases were studied using chemically distinct substrates. Additionally, the structural and mechanical properties of the amyloidotic peptides associated with diseases: transthyretin (cardiac amyloidosis), tau and Aβ proteins (Alzheimer’s disease) were studied using MD simulations. The results gleaned from these studies will advance scientific efforts to develop small molecules inspired by the active sites of these proteins for application in bioremediation and medicine.