Is hairpin formation in single-stranded polynucleotide diffusion-controlled?

An intriguing puzzle in biopolymer science is the observation that single-stranded DNA and RNA oligomers form hairpin structures on time scales of tens of microseconds, considerably slower than the estimated time for loop formation for a serniflexible polymer of similar length. To address the origin of the slow kinetics and to determine whether hairpin dynamics are diffusion-controlled, the effect of solvent viscosity (y) on hairpin kinetics was investigated using laser temperature-jump techniques. The viscosity was varied by addition of glycerol, which significantly destabilizes hairpins. A previous study on the viscosity dependence of hairpin dynamics (Wallace et al. Proc. Natl. Acad. Sci. U.S.A. 2000, 98, 5584), in which all the changes in the measured rates were attributed to a change in solvent viscosity, reported an apparent scaling of relaxation times (tau(r)) on eta as tau(r) similar to eta(0.8). In this study, we demonstrate that if the effect of viscosity on the measured rates is not deconvoluted from the inevitable effect of change in stability, then separation of tau(r) into opening (tau(o)) and closing (tau(c)) times yields erroneous behavior, with different values (and opposite signs) of the apparent scaling exponents, tau(o) similar to eta(-0.4) and tau(c) similar to eta(1.5). Under isostability conditions, obtained by varying the temperature to compensate for the destabilizing effect of glycerol, both tau(o) and tau(c) scale as similar to eta 1:1 +/- 0.1. Thus, hairpin dynamics are strongly coupled to solvent viscosity, indicating that diffusion of the polynucleotide chain through the solvent is involved in the rate-determining step.