Vasopressin V2 receptor phosphopeptide reshapes the conformational landscape of arrestin-2 beyond C-tail detachment

V2Rpp binding to arrestin-2 broadens energetically accessible interdomain rotation angles, but the experimentally observed large rotation is not strongly favored.

• Why it matters: It is unclear whether C-tail detachment alone explains activation-linked interdomain rotation, or whether the bound phosphorylated GPCR tail reshapes arrestin’s conformational landscape beyond detachment.
• What they did: Enhanced-sampling simulations mapped conformational free-energy landscapes for basal (unbound) and V2Rpp-bound arrestin-2, comparing rotation-angle distributions and the energetic cost of C-tail-detached states.
• The result: V2Rpp increases accessible rotation-angle range versus basal arrestin-2, yet large rotations remain only accessible; C-tail displacement alone does not reproduce this, and C-tail detachment is energetically unfavorable without V2Rpp.

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