Cooperativity, smooth energy landscapes and the origins of topology-dependent protein folding rates.
The relative folding rates of simple, single-domain proteins, proteins whose folding energy landscapes are smooth, are highly dispersed and strongly correlated with native-state topology. In contrast, the relative folding rates of small, Gō-potential lattice polymers, which also exhibit smooth energy landscapes, are poorly dispersed and insignificantly correlated with native-state topology. Here, we investigate this discrepancy in light of a recent, quantitative theory of two-state folding kinetics, the topomer search model. This model stipulates that the topology-dependence of two-state folding rates is a direct consequence of the extraordinarily cooperative equilibrium folding of simple proteins. We demonstrate that traditional Gō polymers lack the extreme cooperativity that characterizes the folding of naturally occurring, two-state proteins and confirm that the folding rates of a diverse set of Gō 27-mers are poorly dispersed and effectively uncorrelated with native state topology. Upon modestly increasing the cooperativity of the Gō-potential, however, significantly increased dispersion and strongly topology-dependent kinetics are observed. These results support previous arguments that the cooperative folding of simple, single-domain proteins gives rise to their topology-dependent folding rates. We speculate that this cooperativity, and thus, indirectly, the topology-rate relationship, may have arisen in order to generate the smooth energetic landscapes upon which rapid folding can occur.
Jewett
Andrew I
AI
Department of Physics, University of California at Santa Barbara, Santa Barbara, CA 93106, USA.
Pande
Vijay S
VS
Plaxco
Kevin W
KW
D007700:Kinetics; D008956:Models, Chemical; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics
D011506:Proteins