“Repurposing nucleic acids as force sensors, motors and actuators”
Under a microscope, cells appear stationary, but in reality, cells are highly dynamic structures that are pulling and pushing on one another and on their surroundings. These pulls and pushes are mediated by minuscule forces – at the scale of tens of piconewtons, less than one-billionth the weight of an apple. For context, a force of 7 pN applied a distance of 1 nm equals 1 kcal/mol. Nonetheless, these forces can have profound biochemical impacts on receptor activation. For example, the rapidly fluctuating forces in a growing embryo alter cell growth and fate by activating different adhesion pathways. Despite the importance of mechanics there are limited methods to study forces at the molecular scale. This is a problem that has been ignored by chemists thus far. My group is addressing this gap in knowledge by developing tools to map and manipulate the molecular forces applied by cells. In this talk, I will describe the development of a suite of molecular tension probes. Tension probes are modular and can be engineered using PEG polymers, oligonucleotides, and proteins. The latest generation of tension probes employ nucleic acids, which provide significant improvements in resolution and allow one to employ signal amplification strategies. I will show exciting new advances that harness fluorescence polarization spectroscopy and super-resolution imaging to provide the highest resolution maps of cell traction forces reported to date. I will also describe the application of these probes in the study of platelet activation, podosome formation, and T cell receptor mechanobiology. Finally, armed with these new tools, I will demonstrate that molecular forces not only give rise to tissue architecture but also to boost the fidelity of information transfer between cells. We dubbed this mechanism mechanical proofreading in analogy to the kinetic proofreading model used to explain the extraordinary fidelity of DNA replication and protein expression. I will show examples of mechanical proofreading in adaptive T cell immunity and platelet coagulation.