Configuration-dependent diffusion dynamics of downhill and two-state protein folding.

Configuration-dependent diffusion (CDD) is important for protein folding kinetics with small thermodynamic barriers. CDD can be even more crucial in downhill folding without thermodynamic barriers. We explored the CDD of a downhill protein (BBL), and a two-state protein (CI2). The hidden kinetic barriers due to CDD were revealed. The increased ~1 k(B)T kinetic barrier is in line with experimental value based on other fast folding proteins. Compared to that of CI2, the effective free-energy profile of BBL is found to be significantly influenced by CDD, and the kinetics are totally determined by diffusion. These findings are consistent with both earlier bulk and single-molecule fluorescence measurements. In addition, we found the temperature dependence of CDD. We also found that the ratio of folding transition temperature against optimal kinetic folding temperature can provide both a quantitative measure for the underlying landscape topography and an indicator for the possible appearance of downhill folding. Our study can help for a better understanding of the role of diffusion in protein folding dynamics.