Construct a Catalyst using the Beta-Peptide Bundle

Abstract

“What I cannot create, I do not understand.” Richard Feynman, 1988. Through the construction of an efficient catalyst using a non-natural material, this research project aims to deepen our understanding of the structural and energetic features that control catalysis. We expect our findings to inform the principles for the design and engineering of both proteinaceous enzymes and artificial catalysts. We set out to use beta-peptides - a unique yet virtually unexplored middle ground between proteins and small molecules - to devise catalysts for the formation or hydrolysis of glycosidic bonds. Beta-peptides are smaller and thus synthetically more tractable than natural proteins; nevertheless, they can still adopt higher order structures inaccessible to small molecules. For example, the Schepartz Laboratory reported previously that the EYYK β-peptide self-assembles into an octameric bundle that displays conformational flexibility and thermodynamic properties similar to natural protein. We therefore build our first generation design around the EYYK scaffold. Each beta-peptide bundle will be characterize by three biophysical techniques. In addition to structural information obtained by X-ray crystallography, two novel assays that evaluate the beta-peptide bundles based on their substrate binding affinity and reaction turnover rate will be carried out. Together these information provide details of the physical and chemical properties of the beta-peptides to guide the iterative design - synthesis - characterization process. The latest results of our first generation beta-peptide bundle, EYBK, will be presented. The utility of two newly developed assays for monitoring binding and turnover will also be discussed in the context of informing catalyst design.