Defects in DNA: Lessons from Molecular Motor Design

5 The degree of localization of structural damage in DNA is computationally investigated in the framework of molecular motors. Damage is induced on DNA hairpins with two and three guanine-cytosine (GC) base pairs by the photoinduced isomerization of their azobenzene containing cap. Light-induced changes in elasticity of such hairpins can be used to transduce photon energy into mechanical work in a single-molecule pulling setup through optomechanical cycles. The maximum extractable work per cycle is, in fact, a good measure of the degree of disruption of the hairpin structure upon isomerization. The extractable work was quantified by means of free-energy reconstruction techniques and several microseconds of molecular dynamics simulations. The maximum work that can be extracted from the 2GC and 3GC systems starting from their native B-DNA conformation (d(O3'-OS') approximate to 16 angstrom) is 2.70 kcal/mol in both cases. The fact that the extractable work does not increase when transitioning from the dimer to the trimer implies that the DNA damage induced by azobenzene isomerization is localized to the two base pairs adjacent to the photoswitchable unit. From the perspective of DNA-based molecular motors, these findings indicate that a dense azobenzene arrangement would be required for effective actuation. From a biological perspective, the results highlight the remarkable ability of the DNA design to mitigate the propagation of damage, thus limiting detrimental effects that this may have on healthy cell function.