Graphic insights into the network basis for heat-gated TRPV1

Non-covalent interactions in bio-macromolecules are individually weak but collectively important. How they take a concerted action in a complex biochemical reaction network to realize their thermal stability and activity is still challenging to study. Here graph theory was used to investigate how the temperature-dependent non-covalent interactions as identified in the structures of the thermo-gated capsaicin receptor TRPV1 could form a systemic fluidic grid-like mesh network with topological grids to maintain the 3D structure of TRPV1 and to govern heat-sensing. The results showed that the heat-evoked melting of the biggest grid may initiate a specific temperature threshold for both channel activation and inactivation. Meanwhile, a thermostable balance between an open state and a putatively inactivated state from the same pre-open closed state may account for heat efficacy and the use-dependent desensitization, which were further stabilized by smaller grids. Altogether, both the biggest and smaller grids may be necessary for the temperature sensitivity. Therefore, this grid thermodynamic model may be broadly significant for the structural thermostability and the functional thermoactivity of biological macromolecules. HighlightsO_LIThermo-driven cyclization or decyclization of a DNA hairpin and a network grid in protein was thermodynamically comparable C_LIO_LIThe temperature thresholds of TRPV1 for channel activation and inactivation were comparable theoretically and experimentally C_LIO_LIThe thermo-sensitivities of TRPV1 for channel activation and inactivation were comparable theoretically and experimentally C_LIO_LIThe grid-based systemic thermal instability of TRPV1 was useful to identify different gating states C_LIO_LIThe release of the phosphatidylinositol lipid from the vanilloid site was required for the heat-evoked activation of TRPV1 C_LI