In silico analysis of sodium ion permeation mechanisms in transient receptor potential vanilloid 1.

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel activated by heat, acidity and chemical ligands. While molecular dynamics simulations have shed some light on the cation permeation processes of TRPV1, the mechanisms in the native-state structure under near-physiological conditions remain unestablished. Therefore, the present study conducted molecular dynamics simulations of near-full-length human TRPV1 under a membrane potential of - 100 mV. During permeation events, sodium ions transiently interacted with three binding sites within the channel pore and moved toward the intracellular side. Potential of mean force analyses revealed that sodium ions in the selectivity filter reduced the energy barrier at the hydrophobic gate, facilitating permeation through cooperative interactions. Additionally, mutation of N677, a pre-gate binding site residue, reduced permeation events. Interaction analysis demonstrated that this residue plays an important role in efficient permeation by mediating moderately strong interactions with sodium ions through their coordinated water molecules. These findings highlight the importance of sodium ion accommodation at the selectivity filter and its interaction with N677 for ion permeation through TRPV1. Our data provide new insights into the gating and conduction mechanisms of TRPV1 under near-physiological conditions.