Competition between native topology and nonnative interactions in simple and complex folding kinetics of natural and designed proteins.

We compared folding properties of designed protein Top7 and natural protein S6 by using coarse-grained chain models with a mainly native-centric construct that accounted also for nonnative hydrophobic interactions and desolvation barriers. Top7 and S6 have similar secondary structure elements and are approximately equal in length and hydrophobic composition. Yet their experimental folding kinetics were drastically different. Consistent with experiment, our simulated folding chevron arm for Top7 exhibited a severe rollover, whereas that for S6 was essentially linear, and Top7 model kinetic relaxation was multiphasic under strongly folding conditions. The peculiar behavior of Top7 was associated with several classes of kinetic traps in our model. Significantly, the amino acid residues participating in nonnative interactions in trapped conformations in our Top7 model overlapped with those deduced experimentally. These affirmations suggest that the simple ingredients of native topology plus sequence-dependent nonnative interactions are sufficient to account for some key features of protein folding kinetics. Notably, when nonnative interactions were absent in the model, Top7 chevron rollover was not correctly predicted. In contrast, nonnative interactions had little effect on the quasi linearity of the model folding chevron arm for S6. This intriguing distinction indicates that folding cooperativity is governed by a subtle interplay between the sequence-dependent driving forces for native topology and the locations of favorable nonnative interactions entailed by the same sequence. Constructed with a capability to mimic this interplay, our simple modeling approach should be useful in general for assessing a designed sequence's potential to fold cooperatively.