Protein folding: Binding of conformationally fluctuating building blocks via population selection

Chung Jung Tsai, Buyong Ma, Sandeep Kumar, Haim Wolfson, Ruth Nussinov*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


Here we review different aspects of the protein folding literature. We present a broad range of observations, showing them to be consistent with a general hierarchical protein folding model. In such a model, local relatively stable, conformationally fluctuating building blocks bind through population selection, to yield the native state. The model includes several components: (1) the fluctuating building blocks that constitute local minima along the polypeptide chain, which even if unstable still possess higher population times than all alternate conformations; (2) the landscape around the bottom of the funnels; (3) the consideration that protein folding involves intramolecular recognition; (4) similar landscapes are observed for folding and for binding, and that (5) the landscape is dynamic, changing with the conditions. The model considers protein folding to be guided by native interactions. The reviewed literature includes the effects of changing the conditions, intermediates and kinetic traps, mutations, similar topologies, fragment complementation experiments, fragments and pathways, focusing on one specific well-studied example, that of the dihydrofolate reductase, chaperones, and chaperonines, in vivo vs. in vitro folding, still using the dihydrofolate example, amyloid formation, and molecular "disorder". These are consistent with the view that binding and folding are similar events, with the differences stemming from different stabilities and hence population times.

Original languageEnglish
Pages (from-to)399-433
Number of pages35
JournalCritical Reviews in Biochemistry and Molecular Biology
Issue number5
StatePublished - 2001


FundersFunder number
Hermann Minkowski-MINERVA Center for Geometry
Ministry of Sci ence grant
National Institutes of HealthNO1-CO-56000
National Cancer Institute
Israel Academy of Sciences and Humanities
Israel Science Foundation
Tel Aviv University


    • Binding
    • Conformational ensembles
    • Dynamic landscapes
    • Folding
    • Funnels
    • Induced conformational change


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