Professor
Thomas C. Jenkins Department of Biophysics
Krieger School of Arts & Sciences

grose@jhu.edu

202 Jenkins Hall
3400 N. Charles Street
Baltimore, MD 21218

Office: 410-516-7244
Lab: 410-516-6889

Under physiological conditions, a protein undergoes a spontaneous disorder order transition called folding. The protein polymer is highly flexible when unfolded but adopts its unique native, three-dimensional structure when folded. Current experimental knowledge comes primarily from thermodynamic measurements in solution or the structures of individual molecules, elucidated by either X-ray crystallography or NMR spectroscopy. From the former, we know the enthalpy, entropy and free energy differences between the folded and unfolded forms of hundreds of proteins under a variety of solvent/co-solvent conditions. From the latter, we know the structures of ~40,000 proteins, which are built on scaffolds of hydrogen-bonded structural elements, ?-helix and ?-sheet. Anfinsen showed that the amino acid sequence alone is sufficient to determine a proteins structure, but the molecular mechanism responsible for selfassembly remains an open question perhaps the most fundamental open question in biochemistry. In the current mideset, developed over the past half-century, the energetics of sidechain interactions dominate the folding process, driving the chain to self-organize under folding conditions.

Our recent re-evaluation of these ideas has led to an alternative model that inverts the prevailing sidechain/backbone paradigm. Here, the energetics of backbone hydrogen bonds dominate the folding process, with substantial pre-organization in the unfolded state. Then, under folding conditions, the resultant fold is selected from a limited repertoire of structural possibilities, each corresponding to a distinct hydrogen-bonded arrangement of ?-helices and/or strands of ?-sheet.

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 structural 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.

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.