Transient, highly populated, building blocks folding model

Chung Jung Tsai, Ruth Nussinov*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


Protein folding is a hierarchical event, in which transiently formed local structural elements assemble to yield the native conformation. In principle, multiple paths glide down the energy landscape, but, in practice, only a few of the paths are highly traveled. Here, the literature is reviewed in this light, and, particularly, a hierarchical, building block protein-folding model is presented, putting it in the context of a broad range of experimental and theoretical results published over the past few years. The model is based on two premises: First, although the local building block elements may be unstable, they nevertheless have higher population times than all alternate conformations; and, second, protein folding progresses through a combinatorial assembly of these elements. Through the binding of the most favorable building block conformers, there is a redistribution of the conformers in solution, propagating the protein-folding reaction. We describe the algorithm, and illustrate its usefulness, then we focus on its utility in assigning simple vs complex folding pathways, on chaperonin-assisted folding, on its relevance to domain-swapping processes, and on its relevance and relationship to disconnectivity graphs and tree diagrams. Considering protein folding as initiating from local transient structural elements is consistent with available experimental and theoretical results. Here, we have shown that, early in the folding process, sequential interactions are likely to take place, even if the final native fold is a complex, nonsequential one. Such a route is favorable kinetically and entiopically. Through the construction of anatomy trees, the model enables derivation of the major folding pathways and their bumps, and qualitatively explains the kinetics of protein folding.

Original languageEnglish
Pages (from-to)209-235
Number of pages27
JournalCell Biochemistry and Biophysics
Issue number2
StatePublished - 2001


  • Building block
  • Disconnectivity graphs
  • Funnels
  • Misfolding
  • Protein folding
  • Sequential folding


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