[ Research Interests ] [ Representative Publications ]

George Rose Professor Department of Biophysics Adjunct Professor Department of Biology B.S. Bard College M.S. Oregon State University Ph.D. Oregon State University

Department of Biophysics Johns Hopkins University 3400 North Charles Street Baltimore, MD 21218-2685 U.S.A. Office Telephone: Lab Telephone: Fax: Email: 410.516.7244 410.516.6889 410.516.4118 grose@jhu.edu Office: 202 Jenkins Hall

Research Interests Conformation and Folding of Proteins and RNA A globular protein will spontaneously self-assemble its components into a highly organized three-dimensional structure under appropriate physiological conditions. Our main goal is to develop a model of protein folding based on physical principles, with particular emphasis on re-evaluating the unfolded state. Protein folding – the reversible transition between the protein's unfolded and folded forms – has been a topic of intense interest during most of the 20th century. At present, the protein data bank holds ~25,000 examples of the folded form, solved by X-ray crystallography and NMR spectroscopy. However, the unfolded form remains elusive. For the past 40 years, the prevailing idea has been that the unfolded population will be broadly distributed over a vast and largely featureless energy landscape. Accordingly, the only way to characterize such a population is statistically. Recently however, a radically different picture of the unfolded state has emerged. In this new view, the ensemble of conformers that contributes most of the unfolded population is surprisingly limited, much of it fluctuating into/out-of polyproline II conformation. These new ideas mandate a thorough re-evaluation of our thinking and conclusions, dating back to early work of Flory and Tanford, a daunting but exciting prospect. Given this background, we are attempting to deconstruct the unfolded population into its structrual and thermodynamic components. Along related lines, we have also been developing a practical algorithm, LINUS, to predict the fold of a protein from its amino acid sequence alone. LINUS is based on the idea that proteins fold hierarchically, starting from the unfolded state. The procedure ascends the folding hierarchy in discrete stages, with further accretion of structure at each step. The chain is represented in full atomic detail and folds under the influence of a simple scoring function. Consistent with our theoretical results, LINUS simulations also indicate that the chain must already exhibit considerable pre-organization in the unfolded state. Further, the simulations provide a physical basis for understanding the early emergence of protein secondary structure (helix, strands, and turns). We have also begun to model the folding of RNA. Here, the conspicuous question is: how can a highly charged helical stack interact favorably with other like-charged stacks? Our approach focuses on the cloud of "territorially" bound counterions around these charged helices (i.e., Manning theory). A favorable entropic gain accompanies the condensation of two such clouds. This idea is an analog of solvent-squeezing in protein folding. There, the hydrophobic effect acts to condense apolar groups, with an associated increase in solvent entropy. In RNA folding, this counterion effect results in condensation of the charged helices, with an associated increase in cation entropy that compensates for unfavorable Coulombic repulsion. Representative Publications Mihaly Mezei, Patrick J. Fleming, Rajgopal Srinivasan, and George D. Rose (2004). The solvation free energy of the peptide backbone is strongly conformation-dependent, Proteins, Structure, Function and Bioinformatics, 55: 502-507. Nicholas C. Fitzkee and George D. Rose (2004). Steric restrictions in protein folding: an ? helix cannot be followed by a contiguous ? strand, Protein Science, 13: 633-639. Nicholas C. Fitzkee and George D. Rose (2004). Reassessing Random-Coil Statistics in Unfolded Proteins. Proc Natl Acad Sci U S A. 101:12497-502. Gong, H., D.G. Isom, R. Srinivasan, and G.D. Rose. (2003). Local secondary structure content predicts folding rates for simple, two-state proteins. J. Mol. Biol. 327:1149-1154. Pappu, R.V. and G.D. Rose (2002). A simple model for polyproline II structure in unfolded states of alanine-based peptides. Prot. Sci. 11:2437-2455. Murthy, V.L., and G.D. Rose. (2000). Is counterion delocalizaton responsible for collapse in RNA folding? Biochemistry 39:14365-14370. Pappu, R.V., R. Srinivasan, and G.D. Rose. (2000). The Flory isolated-pair hypothesis is not valid for polypeptide chains: Implications for protein folding. Proc. Nat. Acad. Sci. 97:12565-12570.

Johns Hopkins University
3400 N. Charles St.
Baltimore, MD 21218

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