Computational biology : methods in automated molecular docking with applications in structural virology and antibody-antigen recognition / Jeffrey Sniffen Taylor.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Taylor, Jeffrey Sniffen.

Contributor:

Burnett, Roger M., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Biochemistry.

Biochemistry--Penn dissertations.

Penn dissertations--Molecular biophysics.

Molecular biophysics--Penn dissertations.

Biochemistry and Molecular biophysics.

Biochemistry and Molecular Biophysics.

Academic Dissertations as Topic.

Medical Subjects:

Biochemistry and Molecular Biophysics.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Biochemistry.

Biochemistry--Penn dissertations.

Penn dissertations--Molecular biophysics.

Molecular biophysics--Penn dissertations.

Biochemistry and Molecular biophysics.

Physical Description:

xi, 239 pages : illustrations ; 29 cm

Production:

1998.

Summary:

Viruses are a particularly interesting class of biological objects for structural study as they can offer unusual opportunities to study the organization of the simplest life forms at atomic level detail. This thesis builds upon the existing body of knowledge on the structure of adenovirus by applying a computational chemistry approach to the structural model of the capsid. A new computer program, "DARWIN," was developed to solve molecular docking problems. DARWIN uses parallel programming techniques and couples a genetic algorithm to the molecular mechanics program "CHARMM," to optimize the conformation and relative orientation for the interesting molecules.

First, DARWIN was used to solve three protein/carbohydrate complexes as test cases. The ligands contained one, three, and four sugar residues, providing an increasing level of flexibility and docking difficulty. In the case of Concanavalin A, DARWIN was able to place the ligand with less than 0.4 A RMS deviation from the crystal structure, and could select other sugars that have been shown to bind in vitro. For antibody fragment Fab Se155-4, DARWIN was able to place the antigen with an RMS deviation of 1.4 A from the crystal structure. The final test docked the GD2 ganglioside to the antibody fragment Fab ME36.1. In this case, a crystal structure of the complex was not available, and therefore the results were compared with a theoretical model of the complex. DARWIN found an alternative solution that fit the criteria used to create the theoretical model, yet had better energy.

The human adenovirus type 2 structure was studied by docking the major structural protein, hexon, to form the viral capsid. Symmetrical substructures of the capsid containing either two or three hexon molecules were modeled, and a model of the capsid was constructed. Comparison of the model with an image reconstruction from cryo-electron micrographs gave good agreement. Specific differences in the two were attributed to the exclusion of minor capsid proteins in the docking experiment. The minor protein pIX was found to play a role in regulating curvature of the capsid and another minor protein, pIIIa, was implicated as the cause of a misalignment of hexons at the facet edges.

Notes:

Supervisor: Roger M. Burnett.

Thesis (Ph.D. in Biochemistry and Molecular biophysics) -- University of Pennsylvania, 1998.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 99-13525.

OCLC:

187478205