Role of Hydrophobic Solvation in TRPV1 Temperature Sensitivity

Abstract

TRPV1, a channel permeable to Ca2+, plays crucial role in pain sensation. The molecular details of TRPV1 gating, including its temperature dependence, remain largely unknown. Here we use a combined computational and experimental approach to shed light on the TRPV1 closed-to-open transition. We find that gating relies on the rotation of N676, an evolutionarily conserved residue on the S6 helix: N676 can either face the channel pore or the S4-S5 linker. Only in the former case, the channel pore is hydrated. When N676 rotates toward the linker, we observe hydration of four so far unreported cavities. Based on our findings, we propose a model for TRPV1 gating involving dynamic hydration of these cavities. Free energy calculations indicate that this gating mechanism is markedly temperature dependent. On the basis of this model, which rationalizes seemingly conflicting experimental observations, we predict and experimentally confirm the behavior of two mutants.