Faculty, Graduate Program
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.
B.S., Chemistry, The Ohio State University, 1988
Ph.D., Chemistry, Cornell University, 1994
P.A. Smith, T.C. Roberts, F.E. Romesberg. Broad-spectrum antibiotic activity of the arylomycin natural products is masked by natural target mutations. (2010) Chem. Biol., 17:1223-1231.
D.A. Malyshev, Y.J. Seo, P. Ordoukhanian, F.E. Romesberg. PCR with an expanded genetic alphabet (2009) J. Am. Chem. Soc. 131:14620-14621.
M.C. Thielges, J. Zimmermann, F.E. Romesberg. Direct observation of ligand dynamics in cytochrome c. (2009) J. Am. Chem. Soc. 131:6054-6055
B.M. O'Neill, S.J. Szyjka, E.T. Lis, A.O. Bailey, J.R. Yates III, O.M. Aparicio, F.E. Romesberg. Pph3-Psy2 is a phosphatase complex required for Rad53 dephosphorylation and replication fork restart during recovery from DNA damage. (2007) Proc. Natl. Acad. Sci. USA, 104:9290-9295.
J. Zimmermann, E.L. Oakman, I.F. Thorpe, X. Shi, P. Abbyad, C.L. Brooks III, S.G. Boxer, F.E. Romesberg. Antibody evolution constrains conformational heterogeneity by tailoring protein dynamics. (2006) Proc. Natl. Acad. Sci. USA, 103:13722-13727.