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STRUCTURAL PREDICTION OF MHC-PEPTIDE-TCR INTERACTIONS:
POTENTIAL FOR VACCINE DESIGN
by
Alexandra J. Schiewe
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHARMACEUTICAL SCIENCES)
May 2007
Copyright 2007 Alexandra J. Schiewe
Object Description
| Title | Structural prediction of MHC-peptide-TCR interactions: potential for vaccine design |
| Author | Schiewe, Alexandra J. |
| Author email | schiewe@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pharmaceutical Sciences |
| School | School of Pharmacy |
| Date defended/completed | 2006-11-29 |
| Date submitted | 2007 |
| Restricted until | Unrestricted |
| Date published | 2007-02-01 |
| Advisor (committee chair) | Haworth, Ian S. |
| Advisor (committee member) |
Hamm-Alvarez, Sarah F. McMillan, Minnie |
| Abstract | Major histocompatibility complex (MHC) molecules are cell surface glycoproteins that bind short peptide fragments and present them to T lymphocytes. The MHC presentation mechanism is a means for the body to identify altered or infected cells, and an immune response is initiated if the T cell receptor (TCR) of the T lymphocyte recognizes the MHC-peptide complex. The importance of the MHC-peptide-TCR interaction has led to the development of computational methods to predict peptides that will bind the MHC molecule with the ultimate goal of selecting candidate peptides for use in immunotherapies, such as peptide-based vaccines, to treat infectious diseases, autoimmune diseases, and cancers. Most of these prediction algorithms use bioinformatic and statistical approaches based on experimental binding affinity data to identify MHC binders. To date, few computational methods incorporating structural approaches have been created for identification of antigenic peptides. Of these methods, most neglect the important contribution of water molecules at the interface as well as the dual interaction of the peptide with the MHC and TCR. The research presented in this dissertation substantiates the use of the PePSSI algorithm (Peptide Prediction of Structure through Solvated Interfaces) for the structural prediction of peptides bound to MHC class I molecules. This algorithm incorporates the important aspect of water molecules at the interface, which form bridging networks between the MHC and peptide. The role of these networks in formation of the MHC-peptide complex as well as other protein-peptide complexes was investigated, and it was found that proper placement of water molecules at a biological interface is energetically favorable and stabilizes the complex. For the MHC-peptide complex, the primary role of these networks is to anchor the peptide backbone within the binding groove.; The PePSSI algorithm was then extended to include the TCR, whose interaction with the peptide is a key factor in immune recognition. Using PePSSI and PePSSI-TCR, antigenic peptides, derived from proteins associated with influenza and cancer, were identified as candidates for the use in peptide-based vaccines. |
| Keyword | MHC-peptide; T cell receptor; structure prediction |
| Language | Spanish |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m237 |
| Contributing entity | University of Southern California |
| Rights | Schiewe, Alexandra J. |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@dots.usc.edu |
| Filename | etd-Schiewe-20070201 |
| Archival file | uscthesesreloadpub_Volume14/etd-Schiewe-20070201.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@dots.usc.edu |
| Full text | STRUCTURAL PREDICTION OF MHC-PEPTIDE-TCR INTERACTIONS: POTENTIAL FOR VACCINE DESIGN by Alexandra J. Schiewe A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PHARMACEUTICAL SCIENCES) May 2007 Copyright 2007 Alexandra J. Schiewe |
