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The sequence-dependent folding landscapes of nucleic acid hairpins reflectmuch of the complexity of biomolecular folding. Folding trajectories, generatedusing single molecule force clamp experiments by attaching semiflexiblepolymers to the ends of hairpins have been used to infer their foldinglandscapes. Using simulations and theory, we study the effect of the dynamicsof the attached handles on the handle-free RNA free energy profile$F^o_{eq}(z_m)$, where $z_m$ is the molecular extension of the hairpin.Accurate measurements of $F^o_{eq}(z_m)$ requires stiff polymers with small$L/l_p$, where $L$ is the contour length of the handle, and $l_p$ is thepersistence length. Paradoxically, reliable estimates of the hopping rates canonly be made using flexible handles. Nevertheless, we show that the equilibriumfree energy profile $F^o_{eq}(z_m)$ at an external tension $f_m$, the force($f$) at which the folded and unfolded states are equally populated, inconjunction with Kramers' theory, can provide accurate estimates of theforce-dependent hopping rates in the absence of handles at arbitrary values of$f$. Our theoretical framework shows that $z_m$ is a good reaction coordinatefor nucleic acid hairpins under tension.

Force Dependent Hopping Rates of RNA Hairpins can be Estimated from Accurate Measurement of the Folding Landscapes