Title

Computational Modeling of the Binding of Amyloid-Beta to Neprilysin for Facilitating the Development of a Potential Alzheimer's Disease Therapy

Defense Date

3-18-2013

Graduation Date

Spring 1-1-2013

Availability

Immediate Access

Submission Type

thesis

Degree Name

MS

Department

Chemistry and Biochemistry

School

Bayer School of Natural and Environmental Sciences

Committee Chair

Michael Cascio

Committee Member

Jeffry Madura

Committee Member

Rita Mihailescu

Keywords

Alzheimer's, Amyloid beta, Computer, model, Molecular dynamic, Neprilysin

Abstract

The zinc metalloprotease neprilysin (NEP) has been shown to degrade small bioactive peptides. Crystal structures of seven NEP-inhibitor complexes and biochemical characterization of NEP activity have highlighted amino acid interactions that are crucial to ligand binding. Studies also indicate that NEP is one of a select group of metalloenzymes that degrade the amyloid-beta peptide (Aß) in vivo and in situ. Accumulation of neurotoxic Aß aggregates in the brain appears to be a causative agent in the pathophysiology of Alzheimer's Disease (AD). For this reason the enzymatic degradation of Aß has been studied extensively, but little is known about specific binding interactions underlying NEP degradation of Aß. Using known crystal structures of NEP, we have conducted comparative computational studies of ligand binding that predict NEP residues Arg 102 and 110 form binding interactions specific to Aß. These interactions may provide insight for using NEP degradation of Aß in AD therapy.

Format

PDF

Language

English

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