Romesberg, Floyd - The Scripps Research Institute

研究领域

Biological and Biophysical Chemistry My research interests are all related to understanding and evolving novel protein function. To this end, we are applying a wide variety of techniques, ranging from synthesis to phage display to femtosecond spectroscopy. Protein Dynamics and Biomolecular Spectroscopy We are developing the use of carbon-deuterium (C–D) bonds to visualize and characterize protein vibrations. We have shown that a single C–D bond may be visualized, and that the frequency and linewidth of the C–D absorption are sensitive to the local protein environment. In addition, we are able to characterize the global flexibility of a protein using three pulse photon echo spectroscopy. This technique is being applied to the study of the process of antibody somatic evolution, protein folding, and polymerase-mediated DNA synthesis, and is used to determine the contribution of protein dynamics and flexibility to biological function. DNA Damage and Repair Mutagenesis is not a random process, but rather, it results from biochemically regulated pathways that the cell induces under times of environmental stress. That cells play the central role in mutation of their own DNA is evidenced by experiments wherein deletion of certain genes causes no ill effect on cell growth, but renders the cells non-mutable in response to DNA damaging agents such as UV light. We are characterizing these inducible mutagenesis pathways in S. cerevisiae, using a combination of genetic and biochemical methods. Expanding the Genetic Code We are working to increase the information capacity of DNA by developing a third base pair, for eventual in vivo application in an unnatural organism that can build proteins with unnatural amino acids. In addition, we are using an activity-based, phage display selection system to optimize the polymerase enzymes that mediate DNA replication so that they accept the unnatural nucleobases as substrates.

近期论文

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Adaptive mutations alter antibody structure and dynamics during affinity maturation. R. Adhikary, W. Yu, M. Oda, T. Chen, R. Walker, R. Stanfield, I. Wilson, J. Zimmermann, F.E. Romesberg, Biochemistry, Accepted for publication 26 February 2015. Axinellamines as broad-spectrum antibacterial agents: scalable synthesis and biology. R.A. Rodriguez, D.B. Steed, Y. Kawamata, S. Su, P.A. Smith, T.C. Steed, F.E. Romesberg, P.S. Baran, J. Am. Chem. Soc., (2014) 136:15403-15413. Evidence of an unusual N-H---N hydrogen bond in proteins. R. Adhikary, J. Zimmermann, J. Liu, R. Forrest, T. Janicki, P. Dawson, S. Corcelli, F.E. Romesberg, J. Am. Chem. Soc., (2014) 136:13474-13477. Systematic exploration of a class of hydrophobic unnatural base pairs yields multiple new candidates for the expansion of the genetic alphabet. K. Dhami, D.A. Malyshev, P. Ordoukhanian, T. Kubelka, M. Hocek, F.E. Romesberg, Nucleic Acids Res, (2014) 42:10235-10244. A semi-synthetic organism with an expanded genetic alphabet. D.A. Malyshev, K. Dhami, T. Lavergne, T. Chen, N. Dai, J.M. Foster, I.R. Corrêa, F.E. Romesberg, Nature (2014) 509:385-388. IR probes of protein microenvironments: utility and potential for perturbation. R. Adhikary, J. Zimmermann, P.E. Dawson, F.E. Romesberg, ChemPhysChem (2014) 15:849-853. Natural-like replication of an unnatural base pair for the expansion of the genetic alphabet and biotechnology applications. L. Li, M. Degardin, T. Lavergne, D. Malyshev, K. Dhami, P. Ordoukhanian, F.E. Romesberg, J. Am. Chem. Soc. (2014) 136:826-829. REVIEW: Directed polymerase evolution. T. Chen, F.E. Romesberg, FEBS Lett., (2014) 588:219-229. REVIEW: Carbon-deuterium bonds as non-perturbative infrared probes of protein dynamics, electrostatics, heterogeneity, and folding. J. Zimmermann, F.E. Romesberg, Methods Mol. Biol., (2014) 1084:101-19. Structural insights into DNA replication without hydrogen bonds. K. Betz, D.A. Malyshev, T. Lavergne, W. Welte, K. Diederichs, F.E. Romesberg, A. Marx, J. Am. Chem. Soc. (2013) 135:18637-18643. Efforts toward broadening the spectrum of arylomycin antibiotic activity. J. Liu, P.A. Smith, D.B. Steed, F.E. Romesberg, Bioorg. Med. Chem. Lett., (2013) 23:5654-5659. REVIEW: Chapter 776 – SpsB Signal Peptidases. D.A. Harris, F.E. Romesberg, Handbook of Proteolytic Enzymes (Third Edition)., N.D. Rawlings, G. Salvesen, Eds. (2013) Volume 3, 3501-3508. Site-specifically arraying small molecules or proteins on DNA using an expanded genetic alphabet. Z. Li, T. Lavergne, D.A. Malyshev, J. Zimmermann, R. Adhikary, K. Dhami, P. Ordoukhanian, Z. Sun, J. Xiang, F.E. Romesberg, Chem. Eur. J., 19:14205-14209 Experimental characterization of electrostatic and conformational heterogeneity in an SH3 domain. R. Adhikary, J. Zimmermann, J. Liu, P.E. Dawson, F.E. Romesberg, J. Phys. Chem. B, 117:13082-13089. Expanding the scope of replicable unnatural DNA: Stepwise optimization of a predominantly hydrophobic base pair. T. Lavergne, M. Degardin, D.A. Malyshev, H.T. Quach, K. Dhami, P. Ordoukhanian, F.E. Romesberg, J. Am. Chem. Soc. (2013) 135:5408-5419. Efficient and sequence-independent replication of DNA containing a third base pair establishes a functional six-letter genetic alphabet. D.A. Malyshev, K. Dhami, H.T. Quach, T. Laveryne, P. Ordoukhanian, A. Torkamani, F.E. Romesberg, Proc. Natl. Acad. Sci. USA (2012) 109:12005-12010. The mechanism of action of the arylomycin antibiotics and the effects of signal peptidase I inhibition. P.A. Smith, F.E. Romesberg, Antimicrob. Agents Chemother. (2012) 56:5054-5060. Protein dynamics and the diversity of the antibody response. R. Adhikary, W. Yu, M. Oda, J. Zimmermann, F.E. Romesberg, J. Biol. Chem. (2012) 287:27139-27147. Yeasts acquire resistance secondary to antifungal drug treatment by adaptive mutagenesis. D. Quinto-Alemany, A. Canerina-Amaro, L.G. Hernández-Abad, F. Machín, F.E. Romesberg, C. Gil-Lamaignere, PLoS ONE (2012) 7:e42279. KlenTaq polymerase replicates unnatural base pairs by inducing a Watson-Crick geometry. K. Betz, D.A. Malyshev, T. Lavergne, W. Welte, K. Diederichs, T.J. Dwyer, P. Ordoukhanian, F.E. Romesberg, A. Marx, Nat. Chem. Biol. (2012) 8:612-614