Metalloproteins, because of their key biological roles, are prime targets for design. However, despite the accumulation of a large body of information about protein structure and function, owing to the lack of comprehensive understanding of the factors governing peptide and protein folding and protein-metal ion interactions, little progress has been made in the design of analogues that can mimic the structural and/or functional properties of metalloproteins. We would like to propose novel metal ion-assisted self-organizing molecular processes for the design of artificial systems in which metal ion complexation is used to direct the self-organization of short polypeptides into stable secondary structure conformations. In addition, we would like to exploit the binding energy of metal ion-ligand interactions in developing a rational method for enhancing the stability of natural proteins. The long term objective of our research program is to develop simple and novel approaches for the design and synthesis of artificial and semisynthetic metalloproteins with tailor-made structure, properties, and functions. the main objective of the research proposed here is to set forth a practical and experimentally verifiable approach for the de novo design of short metallopeptides and proteins that can adopt stable and well-defined solution conformations. These studies will be useful in evaluating factors hypothesized to be important in peptide and protein folding process. In addition, the delineation of a simple and rational approach for enhancement of protein stability would undoubtedly have considerable applications both in medicine and industry. It is our hope that these studies will lead to a better understanding of how metal sites might influence the stability and folding of peptides and proteins as well as contribute to the advancement of the state of the art in metalloprotein design and engineering.
The specific aims of this proposal are to explore the utility of metal ion-assisted self-organizing molecular processes in: I. Developing a rational approach for enhancing protein stability. Site- specific introduction of metal ion binding sites into the alpha-helical regions of natural proteins. II. Controlling peptide architecture. De novo design of metal ion- stabilized beta-hairpin metallopeptides. Toward the evaluation of amino acid preferences and contact-pair requirements in beta-sheet structures.
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