Dr. George Rose
Professor, Biophysics

Johns Hopkins University
Department of Biophysics
3400 North Charles Street
Baltimore, MD 21218
410-516-7244 Office
410-516-4118 Fax
grose@jhu.edu
Lab Home Page

 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 20^th 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.

Selected Publications:

• Gong, H., Y. Shen, and G.D. Rose (2007) Building native protein conformation from NMR backbone chemical shifts using Monte Carlo fragment assembly. Protein Sci. 16:1515-1521.
• Street, T.O., N.C. Fitzkee, L.L. Perskie, and G.D. Rose (2007) Physical-chemical determinants of turn conformations in globular proteins. Protein Sci. 16:1720-1727.
• Rose, G.D., P.J Fleming, J.R. Banavar, and A. Maritan (2006) A
• backbone-based theory of protein folding. Proc. Nat. Acad. Sci. 103:16623-16633.
• Fleming, P.J., H. Gong, and G.D. Rose. (2006) Secondary structure determines protein topology. Protein Sci. 15:1829-1834.
• Street, T.O., D.W. Bolen, and G.D. Rose. (2006) A molecular mechanism for osmolyte-induced stability. Proc Nat. Acad. Sci. 103:13997-14002.
• Rose, G.D. (2006) Lifting the lid on helix-capping. (News & Views) Nat. Chem. Biol. 2:123-124.
• Street, T.O., G.D. Rose, and D. Barrick. (2006) The role of introns in repeat protein gene formation. J. Mol. Biol. 360:258-266.
• Rose, G.D. (2005) Secondary structure calculations in protein analysis. Encyclopedia of Biological Chemistry 4:1-6, Academic Press/Elsevier Science.
• Fleming, P.J., and G.D. Rose. (2005) Conformational Properties of Unfolded Proteins, Protein Folding Handbook, (Eds. Thomas Kiefhaber and Johannes Buchner), Part 1, Vol. 2, Chapter 20, pp 710-736, Wiley-VCH (Weinheim).
• Fleming, P.J., N.C. Fitzkee, M. Mezei, R. Srinivasan, and G.D. Rose. (2005) A novel method reveals that solvent water favors polyproline II over b-strand conformation in peptides and unfolded proteins: Conditional Hydrophobic Accessible Surface Area (CHASA). Protein Sci. 14:111-118.
• Fitzkee, N.C., H. Gong, P.J. Fleming, N. Panasik, Jr., T.O. Street, and G.D. Rose. (2005) Are proteins made from a limited parts list? Trends Biochem. Sci. 30:73-80.
• Fitzkee, N.C., P.J. Fleming, and G.D. Rose. (2005) The protein coil library: a structural database of non- helix, non-strand fragments derived from the PDB. Proteins 58:852-854.
• Fleming, P.J., and G.D. Rose (2005) Do all backbone polar groups in proteins form hydrogen bonds? Protein Sci. 14:1911-1917.
• Gong, H., and G.D. Rose (2005) Does secondary structure determine tertiary structure in proteins? Proteins 61:338-343.
• Fitzkee, N.C., and G.D. Rose (2005) Sterics and solvation winnow accessible conformational space for proteins. J. Mol. Biol. 353:873-887.
• Gong, H., P.J. Fleming, and G.D. Rose (2005) Building native protein conformation from highly approximate backbone torsion angles. Proc. Nat. Acad. Sci. 102:16227-16232.
• Panasik, Jr., N., P.J. Fleming, and G.D. Rose (2005) Hydrogen-bonded turns in proteins: the case for a recount. Protein Sci. 14:2910-2914.