A letter to Dr. Mandala, Professor McKinnon and the research team

Dear Dr. Mandala, Professor MacKinnon and the research team,

Greetings.

We have carefully read your group’s 2025 PNAS paper Electric-field-induced pore constriction in human Kv2.1 channels. We highly recognize the raw experimental observations and conformational snapshots obtained by your team using cryo-electron microscopy.

While fully respecting the original experimental facts, we hold a different academic perspective regarding the interpretative framework of S4-helix reciprocating sliding and paddle-style gating dynamics adopted in your manuscript. We have identified theoretically inconsistent contradictions of this model with respect to mechanical constraints, motion logic, and physiological discrepancies between artificial vesicle systems and real cell membranes.

Based on long-term research on ion-channel mechanisms, we have developed a novel falsifiable and quantitatively testable origami-windmill cooperative gating model. A complete manuscript presenting our discussion is attached to this email.

This work does not negate or question your experimental data. Instead, it puts forward corrective discussions concerning interpretative biases and paradigm-level limitations of the classical paddle model, and provides a new plausible explanatory framework together with decisive experimental verification schemes for your team’s academic reference.

This manuscript has now been formally submitted to PNAS.

We do not expect a reply nor insist on consensus. Guided by the pursuit of scientific truth, we merely offer an independent and alternative academic viewpoint. Scientific progress stems from diverse discussions, and we hope our work can serve as a useful reference for improving mechanistic understanding within this field.

With best regards for your research,

Sincerely,

Sun Zuodong

论文下载：PNAS-On the Cryo-EM Conformational Observations of Kv2.1 Channels.pdf