Downhill versus two-state protein folding in a statistical mechanical model

Abstract

The authors address the problem of downhill protein folding in the framework of a simple statistical mechanical model, which allows an exact solution for the equilibrium and a semianalytical treatment of the kinetics. Focusing on protein 1BBL, a candidate for downhill folding behavior, and comparing it to the WW domain of protein PIN1, a two-state folder of comparable size, the authors show that there are qualitative differences in both the equilibrium and kinetic properties of the two molecules. However, the barrierless scenario which would be expected if 1BBL were a true downhill folder is observed only at low enough temperature.

Downhill versus Barrier-Limited Folding of BBL

“…Native-centric Go model simulations suggest that the 1BBL and 2CYU NMR structures lead to relatively low free energy barriers for folding, [15][16][17][18] thus supporting the downhill scenario. Similar studies based on the more compact 1W4H NMR structure reached opposite conclusions, 16,18 supporting two-state folding.…”

Probing Possible Downhill Folding: Native Contact Topology Likely Places a Significant Constraint on the Folding Cooperativity of Proteins with ∼40 Residues

“…[22][23][24] These discoveries sparked intense interest. Notwithstanding the ongoing controversy regarding whether BBL is indeed a downhill folder, [25][26][27][28][29] investigations of BBL, λ 6-85 mutants, and other putative downhill-folding proteins have led to significant experimental [30][31][32][33] as well as theoretical [34][35][36][37][38][39][40][41][42] advances (see Refs. 43,44 for reviews).…”

An experimental survey of the transition between two-state and downhill protein folding scenarios

“…Indeed, the fast folder lambda repressor has been shown to fold by either two-state, framework intermediate, or downhill mechanisms, depending on solvent conditions and sequence (6,9,13,19,20). Models for protein BBL, another fast folding protein, also indicate that it folds either in a two-state or downhill manner, depending on the exact sequence and solvent conditions (21,22).The diversity of observations suggests that criteria for downhill folding can be developed only by examining a large number of fast-folding proteins. Here, we take a survey approach to the experimental study of downhill folding.…”