Physics of Biology

   

On the Cryo-EM Conformational Observations of Kv2.1 Channels: A Discussion on the Tetrameric Cooperative Hinge-Sliding Model and the Optimal Origami-Windmill Rotational Gating Hypothesis

Authors: Sun Zuodong

Mandala & MacKinnon published work in PNAS in 2025, in which cryo-electron microscopy (cryo-EM) was employed to capture multiple conformations of the human Kv2.1 potassium channel. They proposed a hinge-sliding gating scenario featuring stepwise cooperative downward displacement of voltage-sensing domains (VSDs): the pore remains permeable when two VSDs undergo displacement, and pore closure occurs only after all four VSDs are fully positioned. The study incorporated these conformational patterns into the S4 "paddle model" framework and attempted to generalize observations obtained from vesicle systems as the fundamental universal mechanism for voltage-gated potassium channels and even neuronal bioelectrical generation.This paper fully acknowledges the authenticity of the original cryo-EM conformational data reported in that study. Nevertheless, it demonstrates that the reconstituted vesicle system is an artificially constructed unidirectional hyperpolarization-limit system containing only Kv2.1. The −40u202fmV and −145u202fmV potentials within the system are drift potentials generated by outward Ku207a efflux along the concentration gradient without counterbalancing sodium ions. The potential-formation logic and ionic balance relationships differ from the physical boundary conditions of physiological action potentials with bidirectional Nau207a-Ku207a coupling and oscillating potentials in native squid giant axon membranes. Meanwhile, the classical interpretation of high-frequency axial sliding of S4 encounters mechanical-dissipation difficulties originating from nanoscale viscous damping. The original paper itself contains uncertainties such as insufficient resolution of the closed-state structure and unclear VSD behaviors under strong hyperpolarization.To distinguish observations from artificial systems from native physiological rules, this paper designs falsifiable control experiments to test whether the stepwise pattern "pore remains open upon displacement of two VSDs" can be reproduced in native excitable membranes. Under existing physical, energetic and physiological constraints, this paper further argues that the origami-windmill impeller rotational gating represents the optimal mechanical solution under the set of constraints. This model intrinsically separates independent ion-entry portals and sphincter-style exit orifices, enabling ordered passage of sodium and potassium ions through distinct pathways without enforced co-entry and co-exit. Such rotational mechanism can further echo the topological logic of DNA double-strand pairing, providing a unified framework for thinking about shared underlying topological rules of coiling, engagement and phase-matching between ion channels and genetic macromolecules. The windmill hypothesis offers an alternative path for subsequent experimental verification in investigations of voltage-gated channel mechanisms.

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[v1] 2026-10-23 22:59:38

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