研究领域

Biochemistry/Organic Chemistry

My group uses de novo design and protein engineering to prepare artificial model proteins that can perform a desired function. The purpose of this effort is twofold: first, by reproducing the main properties and functions of natural proteins in a model system, one can test iteratively hypotheses on the specific contribution of each amino acid to the protein activity; second, once the key principles are elucidated, it will be possible to design novel proteins with activities beyond those of natural proteins. Methods utilized include computational modeling, solid phase synthesis, molecular biology techniques and enzymatic screening. Current projects in the lab are divided in three main areas: Artificial metalloproteins for solar to fuel energy conversion The conversion of solar energy to usable fuel requires the assembly of a specialized chain of reactions, each typically facilitated by a metallic active site. To obtain the necessary spatial organization, we designed a family of peptides that can self assemble into large complexes functionalized with specialized active sites. We are using a variety of artificial amino acid and natural ligands to engineer [Fe4S4] clusters, diiron clusters, and manganese sites in scaffolding peptides. The ultimate goal is to catalyze biomimetic reactions such as water splitting, CO2 reduction, and hydrogen production. Design of membrane proteins Membrane proteins function as gateways to the cell, and are crucial in a number of processes related to energy transduction and cell signaling. We are interested in learning how to control protein-protein interactions and cofactor binding in the membrane. To that end we have designed a stable, membrane soluble protein that utilizes a metal cofactor, heme, as active site. Engineering novel glycan-binding proteins We are using protein engineering and directed protein evolution to design reagents capable of targeting glycans with high affinity and specificity. The ability of attaching sugars to proteins, called glycosylation, is the most ubiquitous post-translational modification in eukaryotic cells. It is known to have a crucial role in many biological processes, including the immune response, inflammation, and the early stages of bacterial and viral infections. Therefore, the development of specific glycan recognition domains has applications both in basic research and in the diagnosis and therapy of diseases. As part of this effort, we have recently discovered the molecular mechanism of action of a potent anti-HIV protein, cyanovirin, paving the way for the design of improved antiviral proteins. We are members of the EFRC Center for Bio-Inspired Solar Fuel Production (http://solarfuel.clas.asu.edu/ ) and of the Center for Membrane Proteins in Infectious Diseases (MPID, http://cemilinks.asu.edu/mpid/ )

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Sommer D.J, Roy A., Astashkin A., and Ghirlanda G., Modulation of Cluster Incorporation Specificity in a De Novo Iron-Sulfur Cluster Binding Peptide, Peptide Science-Biopolymers, Special Issue in honor of Bill DeGrado, in press Sommer D.J., R. Alcala-Torano, Z. Barhani Dizicheh, and G.Ghirlanda “Design of electron transfer peptides: Towards Functional Materials” T. Groves and A Cortajarena Eds, Protein-based Engineered Nanostructures, Springer, in press Roy A., Sommer D.J., Schmidt R., Brown C., Gust D., Astashkine A., and Ghirlanda G., A De Novo Designed 2[4Fe-4S] Ferredoxin Mimic Mediates Electron Transfer (2014) J. Am. Chem. Soc., 136, 17343-9 Featured as Spotlights Flory JD, Johnson T., Simmons C.R., Ghirlanda G., Liu Y., Yan H., and Fromme P. “Purification and Assembly of Cy5 labeled γ-PNAs into a 3D DNA nanocage” Artificial DNA: PNA & XNA; http://www.tandfonline.com/doi/full/10.4161/1949095X.2014.992181#abstract Sommer DJ, Vaughn MD, and Ghirlanda G. “Protein Secondary-shell Interactions Enhance the Photoinduced Hydrogen Production of Cobalt Protoporphyrin IX”, Chem. Commun., 2014, 50, 15852-15855 DOI: 10.1039/C4CC06700B Shinde S., Binder J., Goyal B., DeMunari S., Woodrum B.W., Levitus M, and Ghirlanda, G.* “A Designed Buried Salt Bridge in a Heterodimeric Membrane Protein” Biopolymers. 2014 102(6):437-43. doi: 10.1002/bip.22564. Wang D., Ghirlanda G., Allen JP* “Water oxidation by a nickel-glycine catalyst” (2014) J Am Chem Soc, 136(29), 10198-201. Flory J.D., Simmons C., Lin S., Johnson T., Andreoni A., Ghirlanda G., Liu Y., Yan H., and Fromme P. “PNA driven engineering (incorporation, assembly, conjugation) of native proteins into DNA nanocages” (2014) J Am Chem Soc, 136 (23), 8283–8295. Bolia A., Woodrum B., Cereda A., Wang X., Ozkan S.B.*, Ghirlanda, G.* “Computational analysis and experimental validation of the glycan-protein interaction in Cyanovirin”, Biophysical Journal (2014) 106, 1142-51 Faiella M., Roy A., Sommer D., and Ghirlanda G.: ”Design of functional proteins: towards fuel production” Invited review for Biopolymers-J.Pep. Sci., (2013) 100, 558-571 Roy A., Serrau I., Astashkin A., and Ghirlanda, G.*: “De novo design of an artificial bis-[Fe4S4]-binding protein” (2013) Biochemistry, 52, 7586-94 Cope S., Shinde S., Best R., Ghirlanda G., and Vaiana S. “Cyclic N-terminal fragment of amylin forms non-amyloid fibers” (2013) Biophysical Journal, 105(7); 1661-1669 Ghirlanda G., “A Recipe for Ligand-Binding Proteins”, News & Views, (2013) Nature 501; 177-178 Woodrum BW, Maxwell J.D., Bolia A., Ozkan S.B., and Ghirlanda G., "The antiviral lectin cyanovirin-N: probing multivalency and glycan recognition through experimental and computational approaches" (2013) Biochemical Society Transactions, 41; 1170-1176. Flory J.D., Shinde S., Lin S., Liu Y., Yan H., Ghirlanda G., and Fromme P.:” PNA-peptide Assembly in a 3D DNA Nanoscaffold at Room Temperature” (2013) J Am Chem Soc. 135(18):6985-93 Roy A., Madden C. and Ghirlanda G*. “Photo-induced hydrogen production in a helical peptide incorporating a [FeFe] hydrogenase active site mimic. Chem Commun. (2012) 48(79):9816-8 Guarise C, Shinde S, Kibler K, Ghirlanda G, Prins LJ,Scrimin P,* “A multivalent HIV-1 fusion inhibitor based on small helical foldamers” (2012) Tetrahedron, 68, 4346-4352. Special Issue: Chemistry of Foldamers Shinde S., Woodrum B., Cordova J.M., Ghirlanda G*. “Modulation of Redox Potential in a Minimalist Heme-Binding Membrane Protein” J Biol Inorg Chem. 2012 Apr;17(4):557-64. G. Ghirlanda, L.Prins and P. Scrimin, “Catalysis by peptide-based enzyme models”, in “Amino Acids, Peptides and Proteins in Organic Chemistry”, H.B. Hughes Ed., Wiley VCH, 2012.