Building Exterior Binding Sites on Peptide Coiled Coils

Colorado State University, Fort Collins CO

Investigators

Abstract

This proposal seeks to further understanding of a broadly useful biopolymer self-assembly unit, the alpha-helical coiled-coil. Despite extensive study of coiled coil design principles, little attention has been focused on interactions at and between coiled coil surfaces. Specific recognition of ligand peptides at coiled coil surfaces is a crucial step in the infection cycle of a broad range of RNA viruses, including many notorious human pathogens. An array of high-resolution X-ray structures demonstrates that recognition often relies on binding a few key ligand side chains, using a relatively focused constellation of coiled coil surface positions. The Kennan group will examine ligand/pocket pairs from HIV, visna, Ebola and mumps, to glean rules for effective binding of buried hydrophobic side chains. The interactions of interest will be displayed using a simple monovalent mimic of the HIV protein. Similar investigations of surface and buried polar interactions will use a recently developed model. Once the portability of these recognition elements is validated, they will move on to designer systems that test programmed recognition patterns. These experiments will establish the first fundamental recommendations for targeted molecular recognition at coiled coil surfaces. Given the tremendous utility of these structures in biology, biotechnology, and materials chemistry, a general tool-set for designing and understanding these interactions will have broad applicability. This project will produce a collection of young scientists with a significant diversity of identity and experience. The ideas and techniques are intrinsically multidisciplinary, applying the molecular level thinking of organic chemistry to the problems of structural biology. Students trained to date reflect a commitment to extending the research experience to undergraduates and underrepresented minorities. All of biology is controlled by assemblies of biomolecules (proteins, DNA, sugars, etc.) that transiently stick together long enough to carry out their assigned biological tasks. The ability to control which molecules stick to each other thus holds promise for control over biology itself. The interactions studied here are central to many viral infections of current public interest (HIV, Ebola, etc.), but they also target a very basic and common protein-protein interface that is a core piece in the larger puzzle of someday acquiring full control over biology's rules for how A sticks to B.