title: Protein folding: binding of conformationally fluctuating building blocks via population selection.
abstract: 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.
authors.affiliation: Intramural Research Support Program--SAIC, Laboratory of Experimental and Computational Biology, NCI-Frederick, MD 21702, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Tsai
authors.forename: B
authors.initials: B
authors.lastname: Ma
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.forename: H
authors.initials: H
authors.lastname: Wolfson
authors.forename: R
authors.initials: R
authors.lastname: Nussinov
mesh_terms: D008958:Models, Molecular; D017510:Protein Folding