“Equipped with his five senses, man explores the universe around him and calls the adventure science” E.P. Hubble It is amazing how much we have learned about the working of our universe by using our five senses and how little we still know about the working of these senses themselves! Even though the molecular mechanism of sight, taste, and smell is known, we still don’t know how the mechanical sensations of touch and hearing function at the molecular level. Mechanosensitive (MS) ion channels, present in membranes, are the molecules that sense membrane tension in all species ranging from bacteria to man. They stay functional even in artificial membranes, indicating that mechanosensation occurs at the protein-lipid interface. In an effort to understand the mechanism of force sensation, the major limitation has been the inability to ‘observe’ the molecular changes occurring in MS channels from the onset of the force. The aim of this proposal is to understand how channel proteins sense mechanical force at the molecular level. A bacterial channel, MscL, will be used as a model for its natural function to couple tension in the membrane to protein conformational changes. Here, on the basis of my recent findings, I propose to build on synthetic biology approaches to develop unique tools to specifically address the MS channel, allowing controlling its activity extrinsically and reversibly. In combination with the spectroscopic techniques, I want to elucidate the mechanism of mechanosensation in MscL by measuring structural changes in the protein and its interaction with the surrounding lipids, starting from the onset of the force. The research will clarify not only the long-standing question of how MscL senses tension, but it will also shed light on the common property of mechanosensitivity among nature’s sensors in higher organisms; transient receptor-potential (TRP) channels, which are involved in hearing, touching and other sensory actions.