The objective of this research program is to understand the relationship between the molecular structure of a polypeptide chain and its ability to fold into a defined, three-dimensional structure. Understanding of the molecular basis for the processes of folding and stability is central to biomedical science and represents one of the fundamental unsolved problems in molecular biology. Most studies on protein folding and stability have focused on the role of amino acid sidechains using site-directed mutagenesis. We propose to diverge from this trend by using the total synthesis of proteins to chemically modify the polypeptide backbone. We believe that systematic variation of the backbone will give new insights into the fundamental forces that stabilize proteins and the processes through which they fold. We have demonstrated the ability to chemically synthesize and introduce backbone modifications into two well-defined protein systems, the GCN-4 coiled coil and the chymotrypsin inhibitor CI- 2. In the context of these two systems, we plan to probe the following interactions. 1) The effects of single (-CONH-) to (- COO-) replacements in the backbone of protein helices. 2) The utility of 'double backbone mutant' cycles on the local backbone interactions in alpha helices. 3) The effects of backbone modifications on non-local interactions using the combinatorial assembly of backbone-engineered peptides. 4) The chemical feasibility of creating all ester polymers with protein-like folding properties. The long-term goal of this work is to merge of the fields of biomimetic and natural product chemistry with molecular biology and protein engineering. The systematic application of the tools of synthetic chemistry of protein molecules will create a new platform for the understanding of the molecular basis of protein function.
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