Mechanosensitive ion channels convert mechanical stimuli into electrical signals. NOMPC, a member of the TRP family, represents a rare case of the force-from-tether model, whose ankyrin repeat (AR) domain may serve as a structural tether for mechanosensation. However, the gating mechanism that links force transmission to pore opening remains unclear. Here, using all-atom molecular dynamics and coarse-grained modeling, we propose a refined twist-to-open model centered on NOMPC and extend its implications across the TRP family. By separating the membrane-normal and membrane-parallel force components through kinematic and dynamic analyzes of NOMPC, we demonstrate that membrane-parallel twisting of the TRP helix efficiently opens the channel, whereas membrane-normal pushing alone does not within the simulation time. To understand the mechanical properties of the AR domain, various types of external force stimuli were applied, and the mechanical responses and contributions of different interactions were systematically investigated. Mechanical profiling of the AR superspring reveals compression-torsion coupling and mechanical heterogeneity: a flexible region buffers external forces, while a rigid region converts pushing into torque, thereby driving TRP domain rotation and pore opening. Extending our analysis across the available structures of TRP channels, we find that the rotation of TRP helices is highly conserved. This indicates that TRP helix twisting acts as a convergence point for multiple stimuli, providing a unified structural basis for the polymodal gating of TRP channels. Overall, our study provides direct mechanistic evidence for the role of twisting in NOMPC gating and proposes a generalizable mechanism that may be applicable across the TRP family.
Duan et al. (2026) studied this question.