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.
| Blanco-Canosa, Juan B; Medintz, Igor L; Farrell, Dorothy et al. (2010) Rapid covalent ligation of fluorescent peptides to water solubilized quantum dots. J Am Chem Soc 132:10027-33 |
| Prasuhn, Duane E; Blanco-Canosa, Juan B; Vora, Gary J et al. (2010) Combining chemoselective ligation with polyhistidine-driven self-assembly for the modular display of biomolecules on quantum dots. ACS Nano 4:267-78 |
| Dirksen, Anouk; Yegneswaran, Subramanian; Dawson, Philip E (2010) Bisaryl hydrazones as exchangeable biocompatible linkers. Angew Chem Int Ed Engl 49:2023-7 |
| Brunel, Florence M; Lewis, John D; Destito, Giuseppe et al. (2010) Hydrazone ligation strategy to assemble multifunctional viral nanoparticles for cell imaging and tumor targeting. Nano Lett 10:1093-7 |
| Boeneman, Kelly; Deschamps, Jeffrey R; Buckhout-White, Susan et al. (2010) Quantum dot DNA bioconjugates: attachment chemistry strongly influences the resulting composite architecture. ACS Nano 4:7253-66 |
| Erlich, Lesly A; Kumar, K S Ajish; Haj-Yahya, Mahmood et al. (2010) N-methylcysteine-mediated total chemical synthesis of ubiquitin thioester. Org Biomol Chem 8:2392-6 |
| Metanis, Norman; Keinan, Ehud; Dawson, Philip E (2010) Traceless ligation of cysteine peptides using selective deselenization. Angew Chem Int Ed Engl 49:7049-53 |
| Shekhter, Talia; Metanis, Norman; Dawson, Philip E et al. (2010) A residue outside the active site CXXC motif regulates the catalytic efficiency of Glutaredoxin 3. Mol Biosyst 6:241-8 |
| Tiefenbrunn, Theresa K; Blanco-Canosa, Juan; Dawson, Philip E (2010) Alternative chemistries for the synthesis of thrombospondin-1 type 1 repeats. Biopolymers 94:405-13 |
| Zeng, Ying; Ramya, T N C; Dirksen, Anouk et al. (2009) High-efficiency labeling of sialylated glycoproteins on living cells. Nat Methods 6:207-9 |
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