Tunable molecular tension sensors reveal extension-based control of vinculin loading

Molecular tension sensors have contributed to a growing understanding of mechanobiology. However, the limited dynamic range and inability to specify the mechanical sensitivity of these sensors has hindered their widespread use in diverse contexts. Here, we systematically examine the components of tension sensors that can be altered to improve their functionality. Guided by the development of a first principles model describing the mechanical behavior of these sensors, we create a collection of sensors that exhibit predictable sensitivities and significantly improved performance in cellulo. Utilized in the context of vinculin mechanobiology, a trio of these new biosensors with distinct force- and extension-sensitivities reveal that an extension-based control paradigm regulates vinculin loading in a variety of mechanical contexts. To enable the rational design of molecular tension sensors appropriate for diverse applications, we predict the mechanical behavior, in terms of force and extension, of additional 1020 distinct designs.