The mellifluous voices at home to heavy metal music in hard-rock cafe, we absorb them all effortlessly and all because of our tip-link, a tiny protein-protein complex in inner ear. In this talk, I shall describe how tip-links, the gating-spring in hearing, first responds to the input mechanical signal from sound stimuli, conveys a small threshold tension to ion-channels to trigger channel opening, and dissipates the overexcitation. In reality, the tension generated from mosquito buzzing is enough to open the mechanogated ion-channel. Everything above we hear is over-excitation for the ion-channels.

Using a combination of single-molecule force-clamp measurements with AFM and home-made Magnetic Tweezer (MT), all-atom Steered Molecular Dynamics, and coarse-grained(CG) simulations, we deciphered that the tip-link interface forms slip-ideal-slip bonds under mechanical tension. The slip bond manifests the force-transmission. Ideal bond interface of tip-links for a wide range of mechanical tension simply indicates an insensitive response to force. A range of external force is dissipated by tip-links in such a manner that the interface failed to distinguish the amplitudes of varying external forces. Tip-link thus does not convey this range of force to ion-channels. At very loud noise, tip-links protects sensory mechanines from permanent damages by temporary disengagement from each other. Further, we noticed instantaneous unfolding of tip-links under tension. Unfoldings are usually associated with the reduction in stiffness of the protein springs, thus we refer these unfoldings as an force-adaptation mechanism of tip-links in hearing.

While deducing the mechanism of atypical slip-ideal-slip behaviour of a spring, we were even more surprised to notice that the intrinsic force-response of individual tip-link interface is slip-catch-slip under tension. Just to remind, catch bond is a counterintuitive phenomenon of a bond that becomes firmer under tensile force. While our SMD results deciphered the molecular cues that facilitate the catch bond, our CG simulations explored that the typical filamentous arrangement of tip-link complex is essential for the characteristic band-block filtering of force. Overall, we deciphered that tip-links serve as band-block filter of force, transmits a low-force range for triggering ion-channel opening, and blocks a large range of tension that we are commonly exposed. At very high-force, tip-link disengages.