Sophistication of beta-Peptide Bundle Form and Function

Yale University, New Haven CT

Investigators

Abstract

With the support of the Organic Dynamics Program in the Chemistry Division and the Biomolecular Systems Program in the Division of Molecular and Cellular Biosciences both at the National Science Foundation, Professor Alanna Schepartz of the Chemistry Department at Yale University will attempt to better understand the non-covalent bond in biopolymers. Professor Schepartz reported the first example of a non-proteinaceous quaternary fold that is both structurally unique and physically well characterized. This "foldein" consists of eight copies of the 12-mer beta-peptide Zwit-1F arranged in a helical bundle whose kinetic and thermodynamic properties are virtually indistinguishable from natural proteins. The experiments in the proposal build on that discovery to explore the origins and determinants of beta-peptide bundle stability and assess the potential of this structure to inform understanding of protein folding and develop sophisticated materials and catalysts. The expectation is that the insight gained from the work will allow beta-peptide foldeins to realize their full potential as tools in biology, nanoscale engineering, and medicine. At the same time, identification of rules governing â-peptide higher order assembly will deepen understanding of folding in natural proteins. Finally, the development of complex and functional beta-foldeins prompts one to question the evolutionary fitness of alpha-amino acid proteins and speculate why the 20 common amino acids have become the building blocks of life. Professor Schepartz will provide valuable teaching and learning opportunities to graduate students, undergraduates, and high school students, while simultaneously advancing discovery at the very highest level. As the research described in this proposal is interdisciplinary, the students involved will master a unique and highly desirable set of disciplines: organic synthesis, peptide chemistry, bioorganic chemistry/chemical biology, and biophysics. This combination of skills and breadth of knowledge will ensure that these students continue to make lasting and valuable contributions to the national and international scientific enterprise. It is noted that in addition that a fraction of the experiments outlined in this proposal are collaborative at multiple levels of the educational ladder. In addition, a subset of the experiments will be included in Chemical Biology for Sophomores Laboratory, a course designed by Professor Schepartz for Yale College students. Finally, Professor Schepartz remains deeply committed to the principles and practices of diversity, having maintained since 1988 a research group with numerous women (> 50%) and underrepresented minority students.