TRPP Ion Channels Function in the π-Conformation Rather Than the α-Conformation

The pi-conformation of PKD2 (TRPP1) supports pore hydration and ion conduction, whereas the alpha-conformation stays dewetted unless the lower gate is widened beyond mammalian TRP ranges.

• Why it matters: The conductive state and gating mechanism of PKD2 are unclear, limiting mechanistic understanding and structure-based drug discovery for ADPKD.
• What they did: Molecular dynamics simulations compared alpha- and pi-conformations of PKD2, assessing pore hydration and ion conduction after small openings of the L677 gate and varying the lower gate width.
• The result: The pi-conformation produced simulated conductance comparable to experimental measurements and was also linked to hydrated conduction in PKD2L1 (TRPP2), challenging the alpha-conformation as the conductive state and supporting an alpha-to-pi activation model.

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