Direct observation of transition paths during the folding of proteins and nucleic acids

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Science  08 Apr 2016:
Vol. 352, Issue 6282, pp. 239-242
DOI: 10.1126/science.aad0637

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How biomolecules fold

In order to fold, biomolecules must search a conformational energy landscape to find low-energy states. There are peaks in the landscape where the molecules must occupy unstable conformations for a short time. Neupane et al. used optical tweezers to observe these transition paths directly for single nucleic acid and protein molecules (see the Perspective by Wolynes). They measured a distribution of times taken to cross the transition path and found that the shape of the distribution agrees well with theory that assumes one-dimensional diffusion over the landscape.

Science, this issue p. 239; see also p. 150


Transition paths, the fleeting trajectories through the transition states that dominate the dynamics of biomolecular folding reactions, encapsulate the critical information about how structure forms. Owing to their brief duration, however, they have not previously been observed directly. We measured transition paths for both nucleic acid and protein folding, using optical tweezers to observe the microscopic diffusive motion of single molecules traversing energy barriers. The average transit times and the shapes of the transit-time distributions agreed well with theoretical expectations for motion over the one-dimensional energy landscapes reconstructed for the same molecules, validating the physical theory of folding reactions. These measurements provide a first look at the critical microscopic events that occur during folding, opening exciting new avenues for investigating folding phenomena.

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