The protein folding problem

Ken A. Dill, Sefika Ozkan, M. Scott Shell, Thomas R. Weikl

Research output: Contribution to journalArticlepeer-review

828 Scopus citations


The "protein folding problem" consists of three closely related puzzles: (a) What is the folding code? (b) What is the folding mechanism? (c) Can we predict the native structure of a protein from its amino acid sequence? Once regarded as a grand challenge, protein folding has seen great progress in recent years. Now, foldable proteins and nonbiological polymers are being designed routinely and moving toward successful applications. The structures of small proteins are now often well predicted by computer methods. And, there is now a testable explanation for how a protein can fold so quickly: A protein solves its large global optimization problem as a series of smaller local optimization problems, growing and assembling the native structure from peptide fragments, local structures first.

Original languageEnglish (US)
Pages (from-to)289-316
Number of pages28
JournalAnnual Review of Biophysics
StatePublished - 2008


  • CASP
  • Folding code
  • Folding kinetics
  • Funnel energy landscapes
  • Structure prediction

ASJC Scopus subject areas

  • Biophysics
  • Bioengineering
  • Cell Biology
  • Structural Biology
  • Molecular Biology
  • General Medicine
  • Biochemistry


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