DNA handles bias force-dependent looping times

Abstract

DNA loop formation is central to gene regulation, and its kinetics depend sensitively on mechanical tension. In both single-molecule experiments and biological settings, this tension is typically transmitted through flanking DNA segments rather than acting directly at the looping sites. Using molecular dynamics simulations of the wormlike chain model, we show that such flanking segments substantially enhance the force dependence of looping, with the effect saturating once their length reaches approximately one DNA persistence length and disappearing when the connection is made flexible. We develop an analytic theory in which the handles extend the effective looping coordinate. This extension is set by two quantities: an equilibrium property of the construct that can be measured without force, and the force-dependent length over which a handle remembers the orientation of its binding site. The resulting theory quantitatively reproduces published optical-tweezer measurements, without adjustable parameters. Furthermore, we demonstrate that the longstanding discrepancy between theory and experiment does not originate from neglected DNA-specific elastic effects, but is explained by the indirect transmission of force through the handles, establishing it as the dominant missing ingredient in the theory of DNA looping under force.

12 pages, 4 figures