Simulations of Protein Refolding and Aggregation Using a Novel Intermediate-Resolution Protein Model

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Title: Simulations of Protein Refolding and Aggregation Using a Novel Intermediate-Resolution Protein Model
Author: Smith, Anne Voegler
Advisors: Carol K. Hall, Chair
Paul F. Agris, Member
Robert M. Kelly, Member
Saad A. Khan, Member
Steven W. Peretti, Member
Abstract: The objective of this thesis is to study the phenomena of amorphousand ordered protein aggregation. For this work, we developed anintermediate-resolution protein model for use with the discontinuousmolecular dynamics algorithm. With this model, we simulatedmulti-protein systems at a greater level of detail than has previouslybeen possible and probed the energetic and structural characteristicsof amorphous and fibrillar protein aggregates.We first developed an intermediate-resolution protein model and testedits ability to produce realistic protein dynamics. Each model residue consists of a three-bead backbone and a single-bead sidechain. Excluded volume, hydrogen bonds, and hydrophobic interactionsare represented by discontinuous potentials. Results show that themodel's backbone motion is limited to realistic regions ofphi-psi conformational space. In a series of simulations ondifferent homopeptides, trends in helicity as a function of residuetype are found to be consistent with results from previous studies.In simulations on a four-peptide system designed to produce a fourhelix bundle, the resulting native structure is consistent withexperimental and previous simulation studies.We then studied the competition between model protein refolding andamorphous aggregation for a model four helix bundle. Assembly of thebundle is found to be optimal within a fixed temperature range, withthe high-temperature boundary a function of the complexity of theprotein (or oligomer) to be folded and the low-temperature boundary afunction of the complexity of the protein's environment. As seenelsewhere, protein folding properties are strongly influenced by thepresence of other proteins, and aggregates have substantial levels ofnative secondary structure.Next we studied the stability, nucleation, and growth of a modelfibril aggregate. The stability of the model fibril is the result ofinter-peptide hydrophobic interactions, as has been suggested byexperimental studies, not of inter-peptide hydrogen bonds. A criticalordered substructure exists that must be present to ensure formationof the fibril. We also suggest, based on the model fibrilstructure, that the characteristic asymmetry of fibrils may be adirect result of the energetics of the system.
Date: 2001-03-14
Degree: PhD
Discipline: Chemical Engineering
URI: http://www.lib.ncsu.edu/resolver/1840.16/5756


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