Design of protein-protein interaction specificity using computational methods and experimental library screening

• Main Author: Chen, Tsan-Chou Scott
• Other Authors: Amy Keating.
• Format: Others
• Language: English
• Published: Massachusetts Institute of Technology 2012
• Subjects: Biology.
• Online Access: http://hdl.handle.net/1721.1/70386

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2012. === Cataloged from PDF version of thesis. === Includes bibliographical references. === Computational design of protein-protein interaction specificity is a powerful tool to examine and expand our understanding about how protein sequence determines interaction specificity. It also has many applications in basic bioscience and biotechnology. One of the major challenges for design is that current scoring functions relying on general physical principles do not always make reliable predictions about interaction specificity. In this thesis I described application of two approaches to address this problem. The first approach sought to improve scoring functions with experimental interaction specificity data related to the protein family of design interest. I used this approach to design inhibitor peptides against the viral bZIP protein BZLF 1. Specificity against design self-interaction was considered in the study. The second approach exploited the power of experimental library screening to characterize a large number of designed sequences at once, increasing the overall probability of identifying successful designs. I presented a novel framework for such library design approach and applied it to the design of anti-apoptotic Bcl-2 proteins with novel interaction specificity toward BH3 peptides. Finally I proposed how these two approaches can be combined together to further enhance our design capabilities. === by Tsan-Chou Scott Chen. === Ph.D.