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As biomolecules such as DNA and proteins fold, they follow certain paths that take them from a disordered state to a folded one. These so-called folding transition paths are extremely brief, so researchers have not been able to analyze them directly by purely experimental methods.
Michael T. Woodside of the University of Alberta and coworkers have now observed and measured biomolecular folding transition paths for the first time by direct experiment alone (Science 2016, DOI: 10.1126/science.aad0637).
They used optical tweezers and force spectroscopy to observe the microscopic diffusive motions of a DNA hairpin and a prion protein dimer as they wiggled their way along folding paths. Optical tweezers use radiation pressure from a laser beam to grab hold of and move molecules, and force spectroscopy measures the molecular forces and displacements that result from those manipulations.
The technique could help researchers classify different types of folding transition paths and uncover the way disease-related biomolecules such as prion proteins misfold.
Up to now, scientists could only estimate folding transition paths by computer modeling or by combining theory with experiment. These approaches depend on assumptions about how folding systems react to shifts in temperature and other changes in conditions. But recent improvements in the time resolution of optical tweezer methods enabled Woodside and coworkers to skip the assumptions and observe transition paths directly.
The researchers used optical tweezers to grab each end of a biomolecule and apply force to change its folding state. By measuring the distance between the two ends of the molecule, the team could monitor changes in the DNA or protein’s length, or “extension,” which serves as a proxy for changes in bond angles that occur as the molecule folds. The researchers use these distances to determine the timing and energy of the folding transition.
“This is truly spectacular work,” says biophysicist William A. Eaton of the National Institutes of Health, an expert in transition-path analysis. His NIH colleague, protein folding specialist Hoi Sung Chung, points out that the averages and distributions of transition times determined in the study agree well with theoretical estimates. The researchers’ “use of advanced optical tweezer technology to successfully measure the transition-path time distributions for the first time in near-perfect agreement with theory is simply amazing,” Chung says.
Thomas Perkins of JILA, in Boulder, Colo., who specializes in single-molecule measurements of biological systems, notes that the DNA hairpin and prion protein dimer have relatively long transition path times, so “the challenge to the field will be to extend the approach to small globular proteins with faster transition path times.”
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