Probe-dependent and nonexponential relaxation kinetics: Unreliable signatures of downhill protein folding

• Published in: Proteins, structure, function, and bioinformatics structure, function, and bioinformatics, 2007-07, Vol.68 (1), p.205-217
• Main Author: Hagen, Stephen J.
• Format: Article
• Language: English
• Subjects: Biophysics - methods; Computational Biology - methods; diffusion; dynamics; fluorescence; Kinetics; landscape; Models, Chemical; Protein Denaturation; Protein Folding; Proteins - chemistry; simulation; stretched exponential
• ISSN: 0887-3585; 1097-0134
• DOI: 10.1002/prot.21342

The theoretical suggestion that some proteins may encounter no significant free energy barriers during their folding raises an important question: What experimental signature does this downhill folding produce? Several authors have argued that nonexponential (and especially stretched exponential) or probe‐dependent kinetics represent useful experimental signatures of a downhill free energy surface. Here we examine more closely the connection between unusual kinetics and downhill energy surfaces. Simulation of diffusive relaxation dynamics on a variety of generically downhill, two‐dimensional free energy surfaces shows that these surfaces do not necessarily produce either probe‐dependent or significantly nonexponential kinetics. Conversely, we find that two‐dimensional surfaces with significant (>3kB T) energy barriers can readily give rise to nonexponential and probe‐dependent kinetics. These results show that downhill folding does not constitute a necessary or sufficient condition for nonexponential and/or probe‐dependent folding kinetics. One cannot easily prove or disprove that a protein folds downhill simply by studying its relaxation kinetics. Proteins 2007. © 2007 Wiley‐Liss, Inc.