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Publication Date

2012-05-25

Availability

UM campus only

Embargo Period

2012-05-25

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Chemistry (Arts and Sciences)

Date of Defense

2012-05-04

First Committee Member

Rajeev Prabhakar

Second Committee Member

Thomas K. Harris

Third Committee Member

James N. Wilson

Fourth Committee Member

David Chatfield

Abstract

In this thesis, innovative theoretical and computational techniques including quantum mechanics (QM), hybrid quantum mechanics/molecular mechanics (QM/MM ONIOM), molecular dynamics (MD) simulations and molecular docking methods are employed to derive the structural and mechanistic information of functioning of proteolytic enzymes (aspartyl proteases and metallopeptidases) and aggregation mechanisms of amyloid beta (Aβ) peptide associated with Alzheimer’s disease (AD). In particular, the enzyme-substrate interactions and substrate hydrolysis mechanisms utilized by these proteolytic enzymes and their synthetic analogues are studied at the atomic level. An alternative strategy to design novel inhibitors for aspartyl proteases and to inhibit the aggregation of the Aβ peptide has also been explored. In addition, the role of the Aβ peptide in the oxidative stress mechanism has been investigated. These studies elucidate the mechanisms of peptide hydrolysis catalyzed by proteases and their synthetic analogues and suggest alternative strategies for the design of novel inhibitors. The results gleaned from these studies will advance scientific efforts to develop therapeutic interventions for the treatment of AD.

Keywords

Aspartyl protease; Peptidase; Amyloid beta; Computational; Molecular dynamics; QM/MM

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