The mechanisms by which proteins fold into their well-defined three-dimensional structures, and function is a problem that we are addressing through de novo protein design. In the previous funding period we focused on design and folding of peptides that assemble into three-helix bundles and four-helix diiron proteins. In the coming period, wewill design models for a number of redox-active proteins to determine how proteins create environments that define the reactivity and catalytic properties of metal ions and organic cofactors. In addition, we will design a series of peptides that change their aggregation state in response to covalent 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 to catalyze 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 the chemical properties of a common diiron center to obtain such a diversity of highly specific catalysts? To address this question, we have designed and structurally characterized several minimal models for diiron iproteins. 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 wil develop novel methods for the design of a variety of helical bundles and b-proteins that encapsulate metal ions, homes, synthetic porphyrins, and linked porphyrin-quinone conjugates.
Aim 3. Design of peptides that change their conformations in response to covalent modifications and binding of small molecules. These peptides will be structurally characterized, and used to control non-covalent interactions such as binding to DNA.
|Molnar, Kathleen S; Bonomi, Massimiliano; Pellarin, Riccardo et al. (2014) Cys-scanning disulfide crosslinking and bayesian modeling probe the transmembrane signaling mechanism of the histidine kinase, PhoQ. Structure 22:1239-51|
|Seither, Katelyn M; McMahon, Heather A; Singh, Nikita et al. (2014) Specific aromatic foldamers potently inhibit spontaneous and seeded A?42 and A?43 fibril assembly. Biochem J 464:85-98|
|Montalvo, Geronda L; Zhang, Yao; Young, Trevor M et al. (2014) De novo design of self-assembling foldamers that inhibit heparin-protein interactions. ACS Chem Biol 9:967-75|
|Gonzalez, Gabriel; Hannigan, Brett; DeGrado, William F (2014) A real-time all-atom structural search engine for proteins. PLoS Comput Biol 10:e1003750|
|Rufo, Caroline M; Moroz, Yurii S; Moroz, Olesia V et al. (2014) Short peptides self-assemble to produce catalytic amyloids. Nat Chem 6:303-9|
|Montalvo, Geronda L; Gai, Feng; Roder, Heinrich et al. (2014) Slow folding-unfolding kinetics of an octameric *-peptide bundle. ACS Chem Biol 9:276-81|
|Pavone, Vincenzo; Zhang, Shao-Qing; Merlino, Antonello et al. (2014) Crystal structure of an amphiphilic foldamer reveals a 48-mer assembly comprising a hollow truncated octahedron. Nat Commun 5:3581|
|Ghosh, Ayanjeet; Wang, Jun; Moroz, Yurii S et al. (2014) 2D IR spectroscopy reveals the role of water in the binding of channel-blocking drugs to the influenza M2 channel. J Chem Phys 140:235105|
|Korendovych, Ivan V; DeGrado, William F (2014) Catalytic efficiency of designed catalytic proteins. Curr Opin Struct Biol 27:113-21|
|Koerber, James T; Thomsen, Nathan D; Hannigan, Brett T et al. (2013) Nature-inspired design of motif-specific antibody scaffolds. Nat Biotechnol 31:916-21|
Showing the most recent 10 out of 74 publications