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Multiple Folding Pathways of the SH3 Domain

Jose M. Borreguero ^*, Feng Ding , Sergey V. Buldyrev ^*, H. Eugene Stanley ^* and Nikolay V. Dokholyan 

^* Center for Polymer Studies and Department of Physics, Boston University, Boston, Massachusetts; and Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Correspondence: Address reprint requests to J. M. Borreguero, E-mail: jmborr{at}bu.edu.

Experimental observations suggest that proteins follow different folding pathways under different environmental conditions. We perform molecular dynamics simulations of a model of the c-Crk SH3 domain over a broad range of temperatures, and identify distinct pathways in the folding transition. We determine the kinetic partition temperature—the temperature for which the c-Crk SH3 domain undergoes a rapid folding transition with minimal kinetic barriers—and observe that below this temperature the model protein may undergo a folding transition by multiple folding pathways via only one or two intermediates. Our findings suggest the hypothesis that the SH3 domain, a protein fold for which only two-state folding kinetics was observed in previous experiments, may exhibit intermediate states under conditions that strongly stabilize the native state.

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