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.
- Robert L. Baldwin and George D. Rose (2013) Molten globules, entropy-driven
conformational change and protein folding. Curr Opin Struct Biol 23:4-10.
- George D. Rose (2013) The open-ended intellectual legacy of GNR in
Biomolecular Forms and Function World Scientific Publishing, Singapore
- George D. Chellapa and George D. Rose (2012) Reducing the dimensionality of the
protein-folding search problem. Protein Science 21:1231-1240.
- Lauren L. Porter and George D. Rose (2012) A thermodynamic definition of protein
domains. Proc. Nat. Acad. Sci. 109:9420-9425.
- Laura S. Itzhaki and George D. Rose (2012) Folding and binding: lingering questions,
emerging answers. Current Opinion in Structural Biology 22:1-3.
- Peter Tompa and George D. Rose (2011) The Levinthal paradox of the interactome. Protein
- Lauren L. Porter and George D. Rose (2011) Comment on "Revisiting the Ramachandran plot from
a new angle". Protein Science 20:1771-1773
- Haipeng Gong, Lauren L. Porter and George D. Rose (2011) Counting peptide-water hydrogen bonds in
unfolded proteins. Protein Science 20:417-427.
- Lauren L. Porter and George D. Rose (2011) Redrawing the Ramachandran plot after inclusion
of hydrogen-bonding constraints. Proc Nat. Acad. Sci. 108:109-113.
- Robert L. Baldwin, Carl Frieden and George D. Rose (2010) Dry molten globule intermediates and the
the mechanism of protein unfolding. Proteins 78:2725-2737.
- Lauren L. Perskie and George D. Rose (2010) Physical-chemical determinants of coil conformations in
globular proteins. Protein Science 19:1127-1136.
- George D. Rose (2009) In Memoriam: Frederic M. Richards. Proteins 75:535-539.
- Lauren L. Perskie, Timothy O. Street and George D. Rose (2008) Structures, basins and energies: A deconstruction
of the Protein Coil Library. Protein Science 17:1151-1161.
- D. Wayne Bolen and George D. Rose (2008) Structure and energetics of the hydrogen-bonded backbone in protein
folding. Annu. Rev. Biochem. 77:339-362.
- Haipeng Gong and George D. Rose (2008) Assessing the solvent-dependent surface area of unfolded proteins
using an ensemble model. Proc Nat. Acad. Sci. 105:3321-3326.
- Haipeng Gong, Yang Shen and George D. Rose (2007) Building native protein conformation from NMR backbone
chemical shifts using Monte Carlo fragment assembly. Protein Science 16:1515-1521.
- Timothy O. Street, Nicholas C. Fitzkee, Lauren L. Perskie and George D. Rose (2007) Physical-chemical determinants
of turn conformations in globular proteins. Protein Science 16:1720-1727.
- George D. Rose, Patrick J. Fleming, Jayanth R. Banavar and Amos Maritan (2006) A backbone-based theory of protein
folding. Proc. Nat. Acad. Sci. 103:16623-16633.
- Timothy O. Street, D. Wayne Bolen and George D. Rose (2006) A molecular mechanism for osmolyte-induced protein stability.
Proc Nat. Acad. Sci. 103:13997-14002. [pdf 1.3M]
- Patrick J. Fleming, Haipeng Gong and George D. Rose (2006) Secondary structure determines protein topology.
Protein Science 15:1828-1834. [pdf 393K]
- Timothy O. Street, George D. Rose and Doug Barrick (2006) The role of introns in repeat protein gene formation.
J. Mol. Biol. 360:258-266. [pdf 588K]
- George D. Rose (2006) Lifting the lid on helix-capping. (News and Views) Nature Chemical Biology
2:123-124. [pdf 123K]
- Haipeng Gong, Patrick J. Fleming and George D. Rose (2005) Building native protein conformation from highly approximate
backbone torsion angles. Proc. Nat. Acad. Sci. 102:16227-16232. [pdf 608K]
- Nick Panasik Jr., Patrick J. Fleming and George D. Rose (2005) Hydrogen-bonded turns in proteins: The case for
a recount. Protein Science 14:2910-2914. [pdf 189K]
- Nicholas C. Fitzkee and George D. Rose (2005) Sterics and solvation winnow accessible conformational space for
unfolded proteins. J. Mol. Biol. 353:873-887. [pdf 595K]
- Haipeng Gong and George D. Rose (2005) Does secondary structure determine tertiary structure in proteins?
- Patrick J. Fleming and George D. Rose (2005) Do all backbone polar groups in proteins form hydrogen bonds?
Protein Science 14:1911-1917.
- Nicholas C. Fitzkee, Patrick J. Fleming and George D. Rose (2005) The Protein Coil Library: A
structural database of nonhelix, nonstrand fragments derived from the PDB. Proteins 58:852-854. [pdf]
- Nicholas C. Fitzkee, Patrick J. Fleming, Haipeng Gong, Nicholas Panasik Jr, Timothy O. Street and George D. Rose
(2005) Are proteins made from a limited parts list? TiBS 30:73-80. [pdf]
- Patrick J. Fleming, Nicholas C. Fitzkee, Mihaly Mezei, Rajgopal Srinivasan and George D. Rose
(2005) A novel method reveals that solvent water favors polyproline II
over β-strand conformation in peptides and unfolded proteins: conditional
hydrophobic accessible surface area (CHASA). Protein Science
14:111-118. [pdf 524K]
- Patrick J. Fleming and George 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).
- George D. Rose (2005) Secondary structure calculations in protein analysis,
Encyclopedia of Biological Chemistry, Academic Press/Elsevier Science.
- Nicholas C. Fitzkee and George D. Rose (2004) Reassessing random-coil statistics in unfolded proteins.
Proc. Nat. Acad. Sci. 101:12497-12502. [pdf 377K]
- Rajgopal Srinivasan, Patrick J. Fleming and George D. Rose (2004) Ab initio protein folding using LINUS.
Methods Enzymol. 383:48-66.
- Mihaly Mezei, Patrick J. Fleming, Rajgopal Srinivasan and George D. Rose (2004)
Polyproline II helix is the preferred conformation for unfolded polyalanine in water.
Proteins: Structure, Function and Bioinformatics 55: 502-507.
- Nicholas C. Fitzkee and George D. Rose (2004) Steric restrictions in protein folding:
an α-helix cannot be followed by a contiguous β-strand. Protein Science 13:
633-639. [pdf 286K]
- Nancy S. Sung, Jeffrey I. Gordon, George D. Rose, Elizabeth D. Getzoff, Stephen J. Kron, David Mumford,
Jos� N. Onuchic, Norbert F. Scherer, DeWitt L. Sumners, and Nancy J. Kopell
(2003) Educating future scientists. Science 301:1485.
- Haipeng Gong, Daniel G. Isom, Ragjopal Srinivasan and George D. Rose (2003) Local
secondary structure content predicts folding rates for simple two-state proteins. J. Mol. Biol. 327:
1149-1157. [pdf 244K]
- Venkatesh L. Murthy and George D. Rose (2003) RNABase: an annotated database of RNA structures.
Nucleic Acids Research 31:502-504.
- Rohit V. Pappu and George D. Rose (2002) A simple model for poly-proline II structure in
unfolded states of alanine-based peptides. Protein Science 11:2437-2455.
- George D. Rose (2002) Getting to know U, in Unfolded Proteins,
Advances in Protein Chemistry (G. Rose, ed.) 62:xv-xxi.
- Yuan Zhu, Gang Xu, Arun Patel, Megan M. McLaughlin, Carol Solverman, Kristin A.
Knecht, Sharon Sweitzer, Ziotong Li, Peter McDonnell, Rosanna Mirabile, Dawn
Zimmerman, Rogely Boyce, Lauren A. Tierney, Erding Hu, George P. Livi, Bryan A.
Wolf, Sherin S. Abdel-Meguid, George D. Rose, Rajeev Aurora, Preston Hensley, Michael
Briggs, and Peter R. Young (2002) Cloning, expression and initial characterization of a
novel cytokine-like gene family. Genomics 80: 144-150.
- Zhengshuang Shi, C. Anders Olson, George D. Rose, Robert L. Baldwin, and Neville R.
Kallenbach (2002) Polyproline II structure in a sequence of seven alanine residues.
Proc. Nat. Acad. Sci. 99: 9190-9195.
- Rajgopal Srinivasan and George D. Rose (2002) Methinks it like a folding curve. Biophysical Chemistry
101-102:167-171. [pdf 192K]
- Rajgopal Srinivasan and George D. Rose (2002) Ab initio prediction of protein structure
using LINUS. Proteins 47: 489-495.
- Teresa Przytycka, Rajgopal Srinivasan and George D. Rose (2002) Recursive Domains in Proteins.
Protein Science 11: 409-417.
- George D. Rose (2001) Perspective (Remembering Ramachandran).
Protein Science 10: 1691-3.
- Venkatesh L. Murthy and George D. Rose (2000) Is counterion delocalization responsible for collapse in RNA folding?
Biochemistry 39: 14365-14370. [pdf 176K]
- Rohit V. Pappu, Rajgopal Srinivasan and George 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. [pdf 296K]
- George D. Rose (2000) Lysozyme among the Lilliputians. Proc Nat. Acad. Sci. 97:
526-528. [pdf 113K]
- Rajgopal Srinivasan and George D. Rose (1999) The physical basis of secondary structure in
globular proteins. Proc Nat. Acad. Sci. 96: 14258-14263. [pdf 151K]
- Venkatesh L. Murthy, Rajgopal Srinivasan, David E. Draper and George D. Rose (1999) A
complete conformational map for RNA. J. Mol. Biol. 291: 313-327. [pdf 818K]
- Huimin Xu, Rajeev Aurora, George D. Rose, and Robert H. White (1999) Identifying two ancient enzymes in Archaea.
Nature Structural Biology 6: 750-754 [pdf 486K]
- Teresa Przytycka, Rajeev Aurora, George D. Rose (1999) A Protein Taxonomy Based on Secondary Structure.
Nature Structural Biology 6: 672-682. [pdf 2M]
- Robert L. Baldwin and George D. Rose (1999) Is protein folding hierarchic? II. Folding
Intermediates and Transition States.
Tibs 24: 77-83. [pdf 485K]
- Robert L. Baldwin and George D. Rose (1999) Is protein folding hierarchic? I. Local Structure and Peptide Folding.
Tibs 24: 26-33. [pdf 223K]