We propose to establish a Center of Biomedical Research Excellence (COBRE) at the University of Delaware (UD): Design of l-Iierarebieal Recognition Motifs. Research directives within this center are aimed at developing recognition elements that encompass atomic-level interactions for structural control from small molecules to proteins to mesoscale assemblies. Novel design paradigms will be developed for the study of small molecule-protein interactions, protein assembly in membrane environments, the construction of artificial glycoprotein scaffolds to display multivalent recognition motifs, and the preparation of peptide-based biomaterials whose structures and functions are responsive to environmental cues. Novel synthetic methodology will be pursued to prepare non-natural amino acids for incorporation into proteins to impart unique structure and function. The proposed COBRE center will create an expertise base withappropriate infrastructure that will address biomedical questions by identifying molecular design principles that bear on questions related to the recognition function of biomolecules and the synthetic capability to control molecular topology. Five subprojects will be carried out that incorporate both fundamental and applied research components. All of these projects require detailed information about the interplay of structural motifs. These motifs range from characteristic macromolecular surfaces, domains, and scaffolds to the functional significance of specific amino acid side chain residues. Importantly, design principles established within each individual project can be applied across all of the projects to enhance current design strategies and further the general understanding of biomolecular recognition. The titles of these projects are: I. Small Molecule (z-helix Mimics; II. Peptide-based Biomaterials with Environmentally Sensitive Morphologies; Ill. Strained Molecules for the Synthesis of Unnatural Amino Acids; IV. Artificial Glycoprotein Architectures for Applications in Materials and Biology and V. Determinants of Stability and Assembly of Integral Membrane Proteins. These projects are proposed by recently hired, tenure-track assistant professors in the Department of Chemistry and Biochemistry (DCB) and the Department of Materials Science and Engineering (MSEG). Broadly speaking, projects I and V are in the area of structural biology, and II and IV are in bioengineering through materials. Project III complements these two general areas by developing novel synthetic methodology for the preparation of non-natural amino acids that will elicit new protein structural and functional features. Importantly, the proposed center will serve tointegrate the newly established Materials Science and Engineering department and the Organic division of the Chemistry and Biochemistry department into biomedical-related research directives within the University. In addition, this Center will strongly complement not only the Protein Structure Initiative (PSI) launched by the NIH, but also other biomedical research efforts on campus and surrounding institutions. Core facilities to be provided as part of this COBRE will enhance those currently being established on campus and serve to strengthen all of the biomedical research efforts at the University of Delaware.
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