Thermoring-based heat activation switches in the TRPV1 biothermometer

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 3D structures of the thermo-gated capsaicin receptor TRPV1 could form a systemic fluidic grid-like mesh network with topological grids constrained as the thermo-rings to govern heat-sensing. The results showed that the heat-evoked melting of the biggest grid initiated a matched temperature threshold to release the lipid from the active vanilloid site for channel activation. Meanwhile, smaller grids were required to stabilize heat efficacy. Altogether, the change in the total grid sizes upon the change in the total noncovalent interactions along the lipid-dependent gating pathway was necessary for the matched temperature sensitivity. Therefore, this grid thermodynamic model may be broadly significant for the structural thermostability and the functional thermoactivity of bio-macromolecules.