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 kriegerDepartment of Biophysics
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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
Krieger-Eisenhower Professor of Biophysics Emeritus
Research Professor

Johns Hopkins University
Department of Biophysics
3400 North Charles Street
Baltimore, MD 21218
410-516-7244 Office
410-516-4118 Fax
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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. 



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