The mechanisms by which proteins fold into their well-defined three-dimensional structures, andfunction is a problem that we are addressing through de novo protein design. In the previous funding periodwe focused on design and folding of peptides that assemble into three-helix bundles and four-helix diironproteins. In the coming period, wewill design models for a number of redox-active proteins to determinehow proteins create environments that define the reactivity and catalytic properties of metal ions and organiccofactors. In addition, we will design a series of peptides that change their aggregation state in response tocovalent modification or binding of small molecules.
Our specific aims are as follows:
Aim 1, Design of proteins that bind diiron cofactors. Diiron proteins use a single di-metal ion cofactor tocatalyze a multitude of processes, including reversible oxygen binding, hydrolytic reactions, iron oxidation,organic radical formation, and oxidation of hydrocarbons. How do the structures of these proteins tune thechemical properties of a common diiron center to obtain such a diversity of highly specific catalysts? Toaddress this question, we have designed and structurally characterized several minimal models for diironiproteins. In the coming period we will determine how systematic changes to the solvent-accessibility,electrostatics, and polarity of the dimetal site affect its reactivity and catalytic properties.
Aim 2. Computational design of proteins that bind a variety of inorganic and organic cofactors. We wildevelop novel methods for the design of a variety of helical bundles and b-proteins that encapsulate metalions, homes, synthetic porphyrins, and linked porphyrin-quinone conjugates.
Aim 3. Design of peptides that change their conformations in response to covalent modifications and bindingof small molecules. These peptides will be structurally characterized, and used to control non-covalentinteractions such as binding to DNA.
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