Denaturants can accelerate folding rates in a class of globular proteins.

We present a lattice Monte Carlo study to examine the effect of denaturants on the folding rates of simplified models of proteins. The two-dimensional model is made from a three-letter code mimicking the presence of hydrophobic, hydrophilic, and cysteine residues. We show that the rate of folding is maximum when the effective hydrophobic interaction epsilon H is approximately equal to the free energy gain epsilon S upon forming disulfide bonds. In the range 1 < or = epsilon H/ epsilon S < or = 3, multiple paths that connect several intermediates to the native state lead to fast folding. It is shown that at a fixed temperature and epsilon S the folding rate increases as epsilon H decreases. An approximate model is used to show that epsilon H should decrease as a function of the concentration of denaturants such as urea or guanidine hydrochloride. Our simulation results, in conjunction with this model, are used to show that increasing the concentration of denaturants can lead to an increase in folding rates. This occurs because denaturants can destabilize the intermediates without significantly altering the energy of the native conformation. Our findings are compared with experiments on the effects of denaturants on the refolding of bovine pancreatic trypsin inhibitor and ribonuclease T1. We also argue that the phenomenon of denaturant-enhanced folding of proteins should be general.