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 Department of Biophysics
Search Biophysics JHU

Thomas C. Jenkins
Department of Biophysics
110 Jenkins Hall
3400 N. Charles Street
Baltimore, MD 21218

Dr. Bertrand Garcia-Moreno E.
Department Chair

410-516-7245 phone
410-516-4118 fax

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

Protein Folding

     For a globular protein, function follows structure.  Under physiological conditions, many proteins undergo 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 ~80,000 proteins, which are built on scaffolds of α-helix and β-sheet, hydrogen-bonded structural elements proposed by Pauling.  In Nobel prize-winning experiments, Anfinsen showed that the amino acid sequence alone is sufficient to determine a protein’s structure; no auxiliary molecular components or addition of energy is needed.  Most proteins self-assemble spontaneously in water with a little salt at physiological temperature.  The molecular mechanism responsible for this self-assembly process remains an open question – probably the most fundamental open question in biochemistry.  Our current mindset tracks back half a century to a hypothesis of Anfinsen: under folding conditions, each protein attains its native state by sliding down a free-energy gradient to the global minimum.  In contrast to this time-honored view, we propose an alternative viewpoint in which the folded state is selected from a limited repertoire of structural possibilities, each corresponding to a distinct hydrogen-bonded arrangement of α‑helices and/or strands of β‑sheet. 


Recent Publications

  1. Robert L. Baldwin and George D. Rose (2014) Frederic Richards: a NAS biographical memoir. [pdf]
  2. Robert L. Baldwin and George D. Rose (2013) Molten globules, entropy-driven conformational change and protein folding. Curr Opin Struct Biol 23:4-10.
  3. George D. Rose (2013) The open-ended intellectual legacy of GNR in Biomolecular Forms and Function World Scientific Publishing, Singapore
  4. George D. Chellapa and George D. Rose (2012) Reducing the dimensionality of the protein-folding search problem. Protein Science 21:1231-1240.
  5. Lauren L. Porter and George D. Rose (2012) A thermodynamic definition of protein domains. Proc. Nat. Acad. Sci. 109:9420-9425.
  6. Laura S. Itzhaki and George D. Rose (2012) Folding and binding: lingering questions, emerging answers. Current Opinion in Structural Biology 22:1-3. [pdf 158K]
  7. Peter Tompa and George D. Rose (2011) The Levinthal paradox of the interactome. Protein Science 20:2074-2079. [pdf 209K]
  8. Lauren L. Porter and George D. Rose (2011) Comment on "Revisiting the Ramachandran plot from a new angle". Protein Science 20:1771-1773 [pdf 285K]
  9. Haipeng Gong, Lauren L. Porter and George D. Rose (2011) Counting peptide-water hydrogen bonds in unfolded proteins. Protein Science 20:417-427. [pdf 1070K]
  10. 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. [pdf 1020K]
  11. 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. [pdf 284K]
  12. Lauren L. Perskie and George D. Rose (2010) Physical-chemical determinants of coil conformations in globular proteins. Protein Science 19:1127-1136. [pdf 167K]
  13. George D. Rose (2009) In Memoriam: Frederic M. Richards. Proteins 75:535-539. [pdf 214K]
  14. 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. [pdf 599K]
  15. 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. [pdf 470K]
  16. 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. [pdf 516K]
  17. 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. [pdf 640K]
  18. 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. [pdf 566K]
  19. 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. [pdf 867K]
  20. 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]
  21. Patrick J. Fleming, Haipeng Gong and George D. Rose (2006) Secondary structure determines protein topology.  Protein Science 15:1828-1834. [pdf 393K]
  22. 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]
  23. George D. Rose (2006) Lifting the lid on helix-capping. (News and Views) Nature Chemical Biology 2:123-124. [pdf 123K]
  24. 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]
  25. 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]
  26. 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]
  27. Haipeng Gong and George D. Rose (2005) Does secondary structure determine tertiary structure in proteins? Proteins 61:338-343. [pdf 179K]
  28. Patrick J. Fleming and George D. Rose (2005) Do all backbone polar groups in proteins form hydrogen bonds? Protein Science 14:1911-1917. [pdf 120K]
  29. 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]
  30. 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]
  31. 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]
  32. 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). [pdf 282K]
  33. George D. Rose (2005) Secondary structure calculations in protein analysis, Encyclopedia of Biological Chemistry, Academic Press/Elsevier Science.
  34. Nicholas C. Fitzkee and George D. Rose (2004) Reassessing random-coil statistics in unfolded proteins. Proc. Nat. Acad. Sci. 101:12497-12502. [pdf 377K]
  35. Rajgopal Srinivasan, Patrick J. Fleming and George D. Rose (2004) Ab initio protein folding using LINUS. Methods Enzymol. 383:48-66. [pubmed]
  36. 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. [pdf 291K]
  37. 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]
  38. Nancy S. Sung, Jeffrey I. Gordon, George D. Rose, Elizabeth D. Getzoff, Stephen J. Kron, David Mumford, José N. Onuchic, Norbert F. Scherer, DeWitt L. Sumners, and Nancy J. Kopell (2003) Educating future scientists. Science 301:1485. [pdf]
  39. 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]
  40. Venkatesh L. Murthy and George D. Rose (2003) RNABase: an annotated database of RNA structures. Nucleic Acids Research 31:502-504. [pdf 294K]
  41. 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. [pdf 466K]
  42. George D. Rose (2002) Getting to know U, in Unfolded Proteins, Advances in Protein Chemistry (G. Rose, ed.) 62:xv-xxi.
  43. 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. [pdf]
  44. 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. [pdf 315K]
  45. Rajgopal Srinivasan and George D. Rose (2002) Methinks it like a folding curve. Biophysical Chemistry 101-102:167-171. [pdf 192K]
  46. Rajgopal Srinivasan and George D. Rose (2002) Ab initio prediction of protein structure using LINUS. Proteins 47: 489-495. [pdf]
  47. Teresa Przytycka, Rajgopal Srinivasan and George D. Rose (2002) Recursive Domains in Proteins. Protein Science 11: 409-417. [pdf 932K]
  48. George D. Rose (2001) Perspective (Remembering Ramachandran). Protein Science 10: 1691-3. [pdf 155K]
  49. Venkatesh L. Murthy and George D. Rose (2000) Is counterion delocalization responsible for collapse in RNA folding? Biochemistry 39: 14365-14370. [pdf 176K]
  50. 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]
  51. George D. Rose (2000) Lysozyme among the Lilliputians. Proc Nat. Acad. Sci. 97: 526-528. [pdf 113K]
  52. 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]
  53. 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]
  54. 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]
  55. Teresa Przytycka, Rajeev Aurora, George D. Rose (1999) A Protein Taxonomy Based on Secondary Structure. Nature Structural Biology 6: 672-682. [pdf 2M]
  56. Robert L. Baldwin and George D. Rose (1999) Is protein folding hierarchic? II. Folding Intermediates and Transition States. Tibs 24: 77-83. [pdf 485K]
  57. Robert L. Baldwin and George D. Rose (1999) Is protein folding hierarchic? I. Local Structure and Peptide Folding. Tibs 24: 26-33. [pdf 223K]
 
 
 

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