Novel methods in computational analysis and design of protein-protein interactions : applications to phosphoregulated interactions

This thesis presents a number of novel computational methods for the analysis and design of protein-protein complexes, and their application to the study of the interactions of phosphopeptides with phosphopeptide-binding domain interactions. A novel protein-protein interaction type, the action-at-a-distance interaction, is described in the complex of the TEM1 P-lactamase with the 3-lactamase inhibitor protein (BLIP). New action-at-a-distance interactions were designed on the surface of BLIP and computed to enhance the affinity of that complex. A new method is described for the characterization and prediction of protein ligand-binding sites. This method was used to analyze the phosphoresidue-contacting sites of known phosphopeptide-binding domains, and to predict the sites of phosphoresidue-contact on some protein domains for which the correct site was not known. The design of a library of variant WW domains that is predicted to be enriched in domains that might have specificity for "pS/pT-Q" peptide ligands is detailed. General methods for designing libraries of degenerate oligonucleotides for expressing protein libraries as accurately as possible are given, and applied to the described WW domain variant library.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Biology.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2007

Author dc:creator

• Joughin, Brian Alan

Advisor dc:contributor.advisor

• Bruce Tidor and Michael B. Yaffe.

• Biology.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/38630

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/38630