Diffusional limits to the speed of protein folding: fact or friction?

Abstract

Proteins fold by diffusional motion, driven by molecular collisions but limited by frictional drag. We then expect that the timescale of simple diffusional motions of the polypeptide chain defines the minimum time, or the maximum rate, for folding phenomena in general. However, such 'speed limits' are very rapid. They far exceed the rate of folding that is observed in even the fastest-folding small proteins. Why do proteins fold much more slowly than the diffusional limits predict? We present experimental evidence that, in addition to solvent friction, internal dissipative forces within a protein can slow the dynamics. These internal friction forces may ultimately set a much more restrictive limit on the speed of folding.