Publication Date




Embargo Period


Degree Type


Degree Name

Doctor of Philosophy (PHD)


Chemistry (Arts and Sciences)

Date of Defense


First Committee Member

Rajeev Prabhakar

Second Committee Member

Françisco M. Raymo

Third Committee Member

Jamie D. Walls

Fourth Committee Member

Akira Chiba


The selective hydrolysis of peptide or amide bond is required in a wide range of biological, biotechnological and industrial applications. There are significant kinetic barriers to these reactions since peptide bonds are extremely stable and possess a half-life for hydrolysis of 350–600 years at room temperature and pH 4–8. Therefore, nature has devised enzymes to rapidly and selectively cleave these bonds under physiological conditions that are known as peptidases. Specifically, metallopeptidases, generate a scaffold capable of binding one or two metal ions to hydrolyze peptide bonds. The studies on metallopeptidases are important to understand the functions of these enzymes and to design their synthetic analogues. In this thesis, state-of-the-art theoretical and computational chemistry techniques including quantum mechanics (QM), hybrid quantum mechanics/molecular mechanics (QM/MM ONIOM), and molecular dynamics (MD) simulations have been utilized to investigate the mechanisms and structures of mononuclear and binuclear metallopeptidases and their synthetic analogues. In particular, the catalytic mechanisms of four different synthetic complexes of mononuclear metallopeptidases and three natural enzymes and their synthetic analogues of binuclear metallopeptidases have been elucidated. These studies have provided the information regarding the conformation of the reactants, ligand environment, and the role of the metal ions. In addition, the structural properties and interactions between amyloid β peptides (Aβ40/Aβ42) and insulin degrading enzyme (IDE) mutants have been explored using MD simulations.


Peptide/amide cleavage; metallopeptidase; synthetic analogues; mechanism; structure