?Protein Folding in the Absence of Free Energy Barriers?
F. Oliva* V. Muñoz
During folding protein molecules must find their native structure by diffusive motions on a complex energy landscape1. The folding motions and landscape topography are inaccessible to classical kinetics, but could be probed by time-resolved experiments of downhill folding2. The difficulty resides in identifying downhill regimes. Stretched exponential decays and kinetic memory effects are only expected when downhill landscapes are rugged3 and could also originate from folding across multiple barriers. Here we tackle the problem by monitoring with nanosecond resolution the dynamics of secondary structure formation and collapse at various stages of one-state folding. One-state folding landscapes are always downhill with a global minimum that moves tracking the unfolding process4. We observe that secondary structure and collapse dynamics exhibit exponential decays with common relaxation times but large differences in amplitude following their probe-dependent equilibrium behaviour.
The smooth topography in BBL demonstrates how Natural selection operates on entire folding landscapes sanding off the inherent roughness of heteropolymers to a bare minimum. Our findings set a high bar for de novo protein design strategies, which typically only target final structures, and support a possible biological role for BBL as molecular rheostat.
1 Bryngelson, J. D., Onuchic, J. N., Socci, N. D. & Wolynes, P. G. Funnels, Pathways, and the Energy Landscape of Protein-Folding - a Synthesis. Proteins: Struct., Funct., Genet. 21, 167-195 (1995).
2. Eaton, W. A. Searching for "downhill scenarios" in protein folding. Proc. Natl. Acad. Sci. USA 96, 5897-5899 (1999).
3. Plotkin, S. S. & Onuchic, J. N. Understanding protein folding with energy landscape theory part II: quantitative aspects. Quarterly Reviews in Biophysics 35, 205-286 (2002).
