Measuring the folding landscape of a harmonically constrained biopolymer

Pioneering studies have shown that the probability distribution of opening length for a DNA hairpin, recorded under constant force using an optical trap, can be used to reconstruct the energy landscape of the transition. However, measurements made under constant force are subject to some limitations. Under constant force a system with a sufficiently high energy barrier spends most of its time in the closed or open conformation, with relatively few statistics collected in the transition state region. We describe a measurement scheme in which the system is driven progressively through the transition by an optical trap and an algorithm is used to extract the energy landscape of the transition from the fluctuations recorded during this process. We illustrate this technique in simulations and demonstrate its effectiveness in experiments on a DNA hairpin. We find that the combination of this technique with the use of short DNA handles facilitates a high-resolution measurement of the hairpin's folding landscape with a very short measurement time.