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Probing the Kinetics of Single Molecule Protein Folding

Vitor B. P. Leite ^*, José N. Onuchic , George Stell  and Jin Wang  

^* Departamento de Física—Instituto de Biociências, Letras e Ciências Exatas, Universidade Estadual Paulista, São José do Rio Preto, Brazil; Department of Physics, Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California; Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York; and State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry of Chinese Academy of Sciences, Changchun, People's Republic of China

Correspondence: Address reprint requests to Vitor B. P. Leite, E-mail: vleite{at}df.ibilce.unesp.br

Correspondence: Address reprint requests to Jin Wang, E-mail: jin.wang.1{at}stonybrook.edu.

We propose an approach to integrate the theory, simulations, and experiments in protein-folding kinetics. This is realized by measuring the mean and high-order moments of the first-passage time and its associated distribution. The full kinetics is revealed in the current theoretical framework through these measurements. In the experiments, information about the statistical properties of first-passage times can be obtained from the kinetic folding trajectories of single molecule experiments (for example, fluorescence). Theoretical/simulation and experimental approaches can be directly related. We study in particular the temperature-varying kinetics to probe the underlying structure of the folding energy landscape. At high temperatures, exponential kinetics is observed; there are multiple parallel kinetic paths leading to the native state. At intermediate temperatures, nonexponential kinetics appears, revealing the nature of the distribution of local traps on the landscape and, as a result, discrete kinetic paths emerge. At very low temperatures, exponential kinetics is again observed; the dynamics on the underlying landscape is dominated by a single barrier. The ratio between first-passage-time moments is proposed to be a good variable to quantitatively probe these kinetic changes. The temperature-dependent kinetics is consistent with the strange kinetics found in folding dynamics experiments. The potential applications of the current results to single-molecule protein folding are discussed.

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