Topology, stability, sequence, and length: Defining the determinants of two-state protein folding kinetics

The fastest simple, single domain proteins fold a million times more rapidl y than the slowest. Ultimately this broad kinetic spectrum is determined by the amino acid sequences that define these proteins, suggesting that the m echanisms that underlie folding may be almost as complex as the sequences t hat encode them. Here, however, we summarize recent experimental results wh ich suggest that (1) despite a vast diversity of structures and functions, there are fundamental similarities in the folding mechanisms of single doma in proteins and (2) rather than being highly sensitive to the finest detail s of sequence, their folding kinetics are determined primarily by the large -scale, redundant features of sequence that determine a protein's gross str uctural properties. That folding kinetics can be predicted using simple, em pirical, structure-based rules suggests that the fundamental physics underl ying folding may be quite straightforward and that a general and quantitati ve theory of protein folding rates and mechanisms las opposed to unfolding rates and thus protein stability) may be near on the horizon.