A library approach to investigate the correlation between peptide rigidity and binding affinity

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The ability of a peptide to serve as an inhibitor depends on the affinity for its targeted protein. With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Matthew Hartman at Virginia Commonwealth University and Dr. Irene Chen at University of California-Santa Barbara to investigate how the molecular rigidities of peptides determine their binding affinities to proteins. This project uses new and powerful technologies to create molecular collections, or libraries, containing trillions of molecules with diverse ranges of defined rigidities. These peptide libraries are tested for their affinities to proteins with rigid binding pockets or with more flexible binding surfaces. The resulting trends will streamline the discovery of peptide molecules that inhibit biologically and clinically important proteins. This project provides opportunities for interdisciplinary research training and career mentoring to a diverse population of graduate and undergraduate students, including students from underrepresented minority groups. In addition, a module is developed that uses Lego construction toys to introduce upper elementary students to the concept and power of molecular diversity.Peptide libraries are powerful storehouses for the development of protein ligands and inhibitors of protein-protein interactions; molecules that are scarce in standard small molecule libraries. This project addresses the potential benefits of introducing conformational constraints into peptide libraries to answer two questions about the relationship of peptide flexibility and target affinity: does rigidification inherently improve binding affinity; and, are high-affinity binders with rigid structures more rare compared to flexible structures of similar affinity within a library? To answer these questions, peptide libraries are created with matched hydrophobicity and sequence diversity, but increasing levels of rigidity. These libraries will be tested against streptavidin (with a compact and rigid binding site and that recognizes contiguous amino acid motifs), and a prototypical SH3 domain (with an extended and flexible binding surface) to study the dependence on the structure of the protein targets. This wholesale analysis of the prevalence of binders and affinities of peptides selected from each library answers the guiding questions concerning the relationship of rigidity to affinity. Dr. Hartman through this project provides training in chemical biology to a diverse group of undergraduate and graduate students at Virginia Commonwealth University. He and his group are also developing the Plickers-based activities to engage elementary school students (including those from underrepresented minority groups) in learning about molecular interactions and mechanisms.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.