Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 49, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2101006118
Keywords
folding; transition states; kinetics; diffusion; optical tweezers
Categories
Funding
- Natural Sciences and Engineering Research Council
- Alberta Innovates Technology Futures
- National Research Council Canada
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By using optical tweezers at high resolution, the dynamics of folding were probed, revealing brief but ubiquitous pauses in the transition states. These pauses were found to be sequence-dependent and position-dependent, providing insights into the key microscopic events during folding.
Biomolecular folding involves searching among myriad possibilities for the native conformation, but the elementary steps expected from theory for this search have never been detected directly. We probed the dynamics of folding at high resolution using optical tweezers, measuring individual trajectories as nucleic acid hairpins passed through the high-energy transition states that dominate kinetics and define folding mechanisms. We observed brief but ubiquitous pauses in the transition states, with a dwell time distribution that matched microscopic theories of folding quantitatively. The sequence dependence suggested that pauses were dominated by microbarriers from nonnative conformations during the search by each nucleotide residue for the native base-pairing conformation. Furthermore, the pauses were position dependent, revealing subtle local variations in energy-landscape roughness and allowing the diffusion coefficient describing the microscopic dynamics within the barrier to be found without reconstructing the shape of the energy landscape. These results show how high-resolution measurements can elucidate key microscopic events during folding to test fundamental theories of folding.
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