Molecular basis of co-operativity in protein folding. III. Structural identification of cooperative folding units and folding intermediates

Kenneth P. Murphy, Vinod Bhakuni, Dong Xie, Ernesto Freire

Research output: Contribution to journalArticlepeer-review


The hierarchical partition function formalism for protein folding developed earlier has been extended through the use of three-dimensional polar and apolar contact plots. For each amino acid residue in the protein, these plots indicate the apolar and polar surfaces that are buried from the solvent, the identity of all amino acid residues that contribute to this shielding, and the magnitude of their contributions. These contact plots are then used to examine the distribution of the free energy of stabilization throughout the protein molecule. Analysis of these data allows identification of co-operative folding units and their hierarchical levels, and the identification of partially folded intermediates with a significant probability of being populated. The overall folding/unfolding thermodynamics of 12 globular proteins, for which crystallographic and experimental thermodynamics are available, is predicted within error. An energetic classification of partially folded intermediates is presented and the results compared to those cases for which structural and thermodynamic experimental information is available. Four different types of partially folded states and their structural energies are considered. (1) Local intermediates, in which only a local region of the protein loses secondary and tertiary interactions, while the rest of the protein remains intact. (2) Global intermediates, corresponding to the standard molten globule definition, in which significant secondary structure is maintained but native-like tertiary structure contacts are disrupted. (3) Extended intermediates characterized by the existence of secondary structure elements (e.g. α-helices) exposed to solvent. (4) Folding intermediates in proteins with two structural domains. The structure and energetics of folding intermediates of apo-myoglobin, α-lactalbumin, phosphoglycerate kinase and arabinose-binding protein are considered in detail.

Original languageEnglish (US)
Pages (from-to)293-306
Number of pages14
JournalJournal of molecular biology
Issue number1
StatePublished - Sep 5 1992


  • co-operativity
  • folding intermediates
  • molten globule
  • protein folding
  • protein thermodynamics

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


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