Programming Mechanical Behaviour in Single DNA Molecules

Synopsis

DNA is a programmable mechanical material. In this talk, I will discuss two complementary strategies for engineering its mechanical behaviour: controlling molecular unfolding pathways and reshaping the mechanical energy landscape, both characterized using single-molecule force spectroscopy.

As an example of engineering force-dependent unfolding pathways, I will present a rationally designed DNA catch bond that strengthens under tension, analogous to biological catch bonds. Its behaviour arises from redirecting how the structure unfolds under force. I will then show our current progress toward the next generation of catch bonds, exploring new molecular architectures that expand the range and tunability of their mechanical responses.

Next, I will discuss how engineering the energy landscape can generate distinct mechanical behaviours within the same molecule. We found that unzipping the same DNA duplex from opposite ends produces markedly different responses despite identical sequence and zero-force free energy. One direction unfolds through a clean two-state transition, whereas the other forms a compliant, force-dependent ensemble of intermediates. This anisotropy arises from asymmetry in the distribution of base-pair stability along the molecule, which reshapes its force-dependent energy landscape. Building on this principle, I will present some new results showing that DNA hairpin compliance, force range, and elasticity can be systematically tuned through design and predicted using a simple model.

Together, these results establish DNA as a programmable material for modulating and detecting molecular forces at cellular interfaces. Finally, I will introduce our latest high-throughput single-molecule force spectroscopy platform, which combines force and fluorescence measurements to accelerate the development and characterization of mechanically programmable DNA molecules.