PROTEIN-FOLDING DYNAMICS - QUANTITATIVE COMPARISON BETWEEN THEORY ANDEXPERIMENT

The development of a quantitative kinetic scheme is a central goal in mechanistic studies of biological phenomena. For fast-folding proteins , which lack experimentally observable kinetic intermediates, a quanti tative kinetic scheme describing the order and rate of events during f olding has yet to be developed. In the present study. the folding mech anism of monomeric lambda repressor is described using the diffusion-c ollision model and estimates of intrinsic alpha-helix propensities. Th e model accurately predicts the folding rates of the wild-type protein and five of eight previously studied Ala <-> Gly variants and suggest s that the folding mechanism is distributed among multiple pathways th at are highly sensitive to the amino acid sequence. For example, the m odel predicts that the wild-type protein folds through a small number of pathways with a folding time of 260 mu s. However, the folding of a variant (G46A/G48A) is predicted to fold through a large number of pa thways with a folding time of 12 mu s. Both folding times quantitative ly agree with the experimental values at 37 degrees C extrapolated to 0 M denaturant. The quantitative nature of the diffusion-collision mod el allows for rigorous experimental tests of the theory.