Research and Teaching Interests
We are interested in the structure-function relationship of natural and non-natural biopolymer systems capable of undergoing Darwinian evolution. This involves an interdisciplinary approach to chemical biology that combines traditional synthetic organic chemistry and molecular biology with genetics, proteomics, and material science. Specific projects in our laboratory include:
- De Novo Evolution of New Protein Folds: Does nature use all possible protein folds or just a subset of protein folds? Current databases of biological protein structures estimate the total number of unique single-domain protein folds to be less than one thousand. Given this astonishingly small number, it seems likely that examples should exist where non-biological protein sequences could adopt a three-dimensional structure that is physically realistic, but not necessarily present in biology. In order to address this problem, we are using mRNA display to select individual protein sequences capable of binding small molecule targets with high affinity and specificity as a way of identifying amino-acid sequences with the potential to form stably folded protein structures. By determining the three-dimensional structure of these proteins, we will begin to examine the extent to which nature samples the total structural diversity available in protein sequence space.
- In Vitro Evolution of TNA Aptamers & Enzymes: Threose nucleic acid (TNA) is a four-carbon sugar analogue of RNA that exhibits complementary Watson-Crick base pairing with DNA, RNA, and other TNA oligonucleotides. This unusual property together with the chemical simplicity of threose, suggest that TNA might be a progenitor candidate of RNA. In order to examine this hypothesis in greater detail, we have developed an in vitro selection strategy for evolving TNA aptamers and enzymes. By comparing the functional properties of TNA with RNA, we aim to determine the fitness of TNA as an alternative genetic material.
Selected Publications
"Searching Combinatorial Libraries for Native Proteins with Novel Folds," J.L. Watkins and J.C. Chaput, ChemBioChem , in Press (2008).
"Synthesis of Two Mirror-Image 4-Helix Junctions Derived from Glycerol Nucleic Acid," R.S. Zhang, E.O. McCullum, and J.C. Chaput, J. Am. Chem. Soc. 130, 5846-5847 (2008).
"Creating Protein Biocatalysts as Tools for Future Industrial Applications," J.C. Chaput, N.W. Woodbury, L.A. Stearns, B.A.R. Williams, Expert Opinion on Biological Therapy , In Press (2008).
"Self-Assembled Peptide Nanoarrays: An Approach to studying Protein-Protein Interactions," B. Williams, K. Lund, Y. Liu, H. Yan., and J.C. Chaput , Angew. Chem. Int. Ed. 46, 3051-3054 (2007).
"Experimental Evidence that GNA and TNA were not Sequential Polymers in the Prebiotic Evolution of RNA," Y-W. Yang, R.S. Zhang, E.O. McCullum, and J.C. Chaput, J. Mol. Evol. 65, 289-295 (2007).
"Structural Insights into the Evolution of a Non-Biological Protein: Importance of Surface Residues in Protein Fold Optimization," M.D. Smith, M.A. Rosenow, M. Wang, J.P. Allen, J.W. Szostak, and J.C. Chaput, PLos One 2, e467 (2007).
"Structure and Evolutionary Analysis of a Non-biological ATP-binding Protein," S.S. Mansy, J. Zhang, R. Kümmerle, M. Nilsson, J.J. Chou, J.W. Szostak and J.C. Chaput, J. Mol. Biol. 371, 501-513 (2007).
"In Vitro Selection of Histone H4 Aptamers for Recognition Imaging Microscopy," L. Lin, D. Hom, S.M. Lindsay, J.C. Chaput, J. Am. Chem. Soc. 129, 14568-14569 (2007).
"Kinetic Analysis of an Efficient DNA-Dependent TNA Polymerase," A. Horhota, Z. Keyong, J.K. Ichida, B. Yu, L.W. McLaughlin, J.W. Szostak and J.C. Chaput, J. Am. Chem. Soc. 127, 7427-7434 (2005).
"Evolutionary Optimization of a Non-Biological ATP-Binding Protein for Improved Folding Stability," J.C. Chaput and J.W. Szostak, Chemistry & Biology 11, 865-874 (2004).
"DNA Polymerase-Mediated TNA Synthesis," J.C. Chaput and J.W. Szostak, J. Am. Chem. Soc 125, 9274-9275 (2003).
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