Zhongbo Yu, Deepak Koirala, Yunxi Cui, Leah F.Easterling, Yuan Zhao, and Hanbin Mao
A 3D folding funnel was proposed in the nineteen nineties to explain the fast kinetics exhibited by a biomacromolecule in presence of seemingly unlimited folding pathways. Over the years, numerous simulations have been performed with this concept, however, experimental verification is yet to attain even for simplest proteins. Here, we have used a click-chemistry based strategy to introduce six pairs of handles in a human telomeric DNA sequence. A laser-tweezers based single-molecule structural fingerprinting on the six inter-handle distances reveals the formation of a hybrid-1 G-quadruplex in the sequence. Kinetic and thermodynamic fingerprinting on the six trajectories defined by each handle-pairs depict a 3D folding funnel and a kinetic topology in which the kinetics pertaining to each handle residue is annotated for this G-quadruplex. We anticipate the methods and the concepts developed here are well applicable to other biomacromolecules, including RNA and proteins.
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