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

Here we review different aspects of the protein folding literature. We pres ent a broad range of observations, showing them to be consistent with a gen eral hierarchical protein folding model. In such a model, local relatively stable, conformationally fluctuating building blocks bind through populatio n selection, to yield the native state. The model includes several componen ts: (1) the fluctuating building blocks that constitute local minima along the polypeptide chain, which even if unstable still possess higher populati on times than all alternate conformations; (2) the landscape around the bot tom of the funnels; (3) the consideration that protein folding involves int ramolecular recognition; (4) similar landscapes are observed for folding an d for binding, and that (5) the landscape is dynamic, changing with the con ditions. The model considers protein folding to be guided by native interac tions. The reviewed literature includes the effects of changing the conditi ons, intermediates and kinetic traps, mutations, similar topologies, fragme nt complementation experiments, fragments and pathways, focusing on one spe cific well-studied example, that of the dihydrofolate reductase, chaperones , and chaperonines, in vivo vs. in vitro folding, still using the dihydrofo late example, amyloid formation, and molecular "disorder". These are consis tent with the view that binding and folding are similar events, with the di fferences stemming from different stabilities and hence population times.