Review Reports - On the Electrically Driven Transition of a Voltage-Sensitive Ion Channel from Insulator to Ion Conductor

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript presents an original and interdisciplinary hypothesis for the mechanism of voltage-sensitive ion channel activation. The author integrates established concepts from physics with current knowledge of ion channel structure and function to propose a novel framework that may help explain several aspects of channel behavior.

As this is a hypothesis paper, it should not be evaluated by the same criteria as an experimental or mechanistic study. While certain elements of the proposed model remain speculative and will require experimental validation, the manuscript succeeds in presenting a coherent and testable hypothesis that can stimulate further investigation. In my view, the value of the work lies in its ability to generate new ideas and motivate experiments designed to evaluate the proposed mechanisms.

The manuscript addresses an important knowledge gap and introduces concepts that may be unfamiliar to many researchers in the ion channel field. However, the interdisciplinary approach is also one of its strengths, as it brings together principles from physics, engineering, and biophysics to offer a fresh perspective on a longstanding problem.

I found the hypothesis intellectually engaging and scientifically thought-provoking. The proposed framework appears to be grounded in established physical principles, and the author has made a commendable effort to connect these principles with existing observations in ion channel biology. Whether all aspects of the hypothesis ultimately prove correct will depend on future experimental studies, but the manuscript provides a useful foundation for such investigations.

Overall, I believe this work makes a meaningful contribution as a hypothesis-generating article. It has the potential to stimulate discussion and inspire new experimental approaches within the ion channel research community. Therefore, I recommend the publication of this manuscript.

Minor revision:

Please define HH as the Hodgkin–Huxley model at its first occurrence in the manuscript
There are unnecessary extra spaces in several places throughout the manuscript. For example, on Page 3, Line 90, the text appears as "laws. It". Please carefully review the entire manuscript and correct all formatting and spacing inconsistencies.
On Page 10, Line 364, the abbreviations Arg and Lys are used. Please define these abbreviations at their first occurrence, which appears on Page 5, Line 183 (Arg = Arginine; Lys = Lysine), and use them consistently throughout the manuscript.

Good luck!

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript proposes the “Channel Activation by Electrostatic Repulsion” hypothesis to explain voltage-sensitive ion channel activation as an electrically driven phase transition from an insulating smectic/ferroelectric state to an ion-conducting chiral nematic state. The topic is within the broad scope of Biophysica, especially theoretical biophysics and biological-system modeling. The manuscript is ambitious and interdisciplinary, and it attempts to connect electrophysiology, electrostatics, ferroelectricity, liquid crystals, and ion-channel function.

However, in its present form, the manuscript does not meet the scientific and presentation standards expected for publication. The central hypothesis is not developed into a sufficiently quantitative, testable, or reproducible theoretical model. Many claims are speculative, several conclusions are overstated relative to the evidence presented, and the manuscript does not adequately engage with current structural and electrophysiological literature on voltage-gated ion channels. The manuscript itself states that it is a “biophysical theory” whose “materials are the laws of physics” and that its methods are the application of existing data to formulate a hypothetical sequence of changes, rather than new experiments or a formal model.

Major Concerns:

Overstatement of conclusions (relevant to manuscript lines 14-31) The manuscript repeatedly presents speculative interpretations as if they are established mechanisms. For example, the abstract claims that critical depolarization eliminates surface charges and dipoles, forms a selectivity-filter dome, causes a proteinquake, generates liquid line defects, and enables ion conduction through transient pathways. These statements should be reframed as hypotheses unless direct experimental or computational evidence is provided.
Insufficient engagement with modern ion-channel structural biology (relevant to manuscript lines 73-82) The manuscript strongly challenges the gated-pore model and states that the traditional formulation has not explained observed phenomena. However, the discussion does not adequately incorporate recent cryo-EM and structure-function literature on voltage-gated sodium and potassium channels, voltage-sensor movement, pore-domain gating, selectivity filters, inactivation states, lipid interactions, and electromechanical coupling. The current literature cannot simply be dismissed as “gated pore assumptions”; the author needs to compare the proposed model directly against available structures and functional data.
The critique of the conventional model is not balanced (relevant to manuscript lines 140-181) The manuscript argues that the gated-pore model contradicts Coulomb’s law and that no water-filled pore has been observed. This is too strong. The conventional model does not require neglect of electrostatics; rather, electrostatic interactions, hydration, ion selectivity, conformational dynamics, and gating-charge movement are central to modern ion-channel biophysics. The author should present a more balanced account of what current models explain, what remains unresolved, and what specific observations the proposed CAbER model explains better.
Reanalysis of historical capacitance data is insufficiently documented (relevant to manuscript lines 241-260) Figure 1 is used to support the claim that squid axon membrane capacitance follows the Curie-Weiss law and indicates ferroelectric behavior. The manuscript should provide the raw data source, fitting procedure, value of C0, fitted parameters, uncertainty estimates, goodness-of-fit statistics, treatment of outliers, and alternative model comparisons. Without these details, the ferroelectric interpretation is not sufficiently supported.
The proposed structural transition lacks molecular specificity (relevant to manuscript lines 421-436) The manuscript proposes a transition from a compact smectic state to a chiral nematic/columnar state, with P loops forming a selectivity-filter dome and line defects serving as ion pathways. However, no atomic-level or coarse-grained structural model is provided. The author should specify which residues, domains, helices, and conformational changes are involved, and how these predictions map onto known sodium or potassium channel structures.
Testable predictions are not clearly defined (relevant to manuscript lines 55-57) The manuscript states that the hypothesis should be experimentally tested and could become a theory if it passes critical tests. However, the paper does not clearly list decisive predictions that would distinguish CAbER from existing models. The author should include a dedicated section with falsifiable predictions, such as expected voltage-dependent dielectric changes, structural expansion amplitudes, optical birefringence signatures, pH effects, isotope effects, mutational consequences, or cryo-EM/MD-observable conformations.

Minor Concerns:

1. Section numbering: The section numbering is inconsistent: the manuscript moves from section 2.2 to 2.4, and some headings are unnumbered.

2. Figure numbering: There appears to be a figure-numbering inconsistency: the text refers to Figure 3, but the following caption is labeled Figure 4.

3. Figure quality and evidential status: Several figures are low-resolution and conceptual rather than evidential. The figure legends should clearly distinguish between experimental data, reanalysis, schematic interpretation, and hypothesis.

4. Reference style: The reference style is inconsistent with MDPI/Biophysica formatting expectations, which normally use bracketed numerical citations in the text.

5. Rhetorical phrasing: Several statements require more precise wording. Phrases such as “the way a nerve impulse travels has long been a scientific mystery” and “progress requires us to abandon that scaffold” should be replaced with specific scientific claims.

Comments on the Quality of English Language

The manuscript contains typographical and language errors, for example “sructure”, “suppots”, “inluding” and inconsistent use of “permittivity”.