Thermoring basis for heat unfolding‐induced inactivation in TRPV1

Abstract Transient receptor potential vanilloid‐1 (TRPV1) is a capsaicin receptor that employs use‐dependent desensitization to protect highly evolved mammals from noxious heat damage in response to repeated or constant heat stimuli. However, the underlying structural factor or motif has not been precisely resolved. In this computational study, the graph theory‐based grid thermodynamic model was used to reveal how temperature‐dependent noncovalent interactions, as identified in the 3D structures of rat TRPV1, could develop a well‐organized fluidic grid‐like mesh network. This network features various topological grids constrained as thermosensitive rings that range in size from the biggest to the smallest, governing distinct structural and functional traits of the channel in response to different temperature degrees. After discovering that heat unfolding of three specific biggest grids, one in the closed state and two in the open state, respectively, causes the reversible activation at 43°C and thermal inactivation between 56°C and 61°C, a smaller random grid was also found to be responsible for irreversible inactivation and use‐dependent desensitization from the pre‐open closed state within the temperature range of 43°C–61°C. Thus, these two distinct inactivation pathways of TRPV1 may be involved in protecting those mammals against noxious heat damage. Key Points A perturbation at the protein–water interface was accompanied by partial heat or cold unfolding of the membrane protein. A reversible or irreversible gating transition of an ion channel may result from a specific or random interaction between two active sites, respectively. Kinetically driven protein aggregation was not the cause of thermodynamically trapped irreversible inactivation, but rather a later stage of partial heat‐induced unfolding.