PONE-D-19-25268

Intramolecular tautomerization of the quercetin molecule via the proton transfer: QM computational study

PLOS ONE

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1. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

- https://www.tandfonline.com/doi/abs/10.1080/07391102.2019.1645734?journalCode=tbsd20

-https://www.tandfonline.com/doi/abs/10.1080/07391102.2019.1656671?journalCode=tbsd20

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

2. Thank you for including the following funding information within the acknowledgements section of your manuscript; "DrSci Ol’ha O. Brovarets’ expresses sincere gratitude to the U.S.-Ukraine Foundation (USUF) Biotech Initiative for a travel grant (“2018 Emerging Biotech Leader of Ukraine”; https://www.usukraine.org/biotechnology-initiative/), enabling to participate in the “63rd Annual Meeting of the Biophysical Society BPS'2019” (Baltimore, Maryland, March 2-6, 2019; https://www.biophysics.org/2019meeting#/; https://bioukraine.org/news/emerging-biotech-leader-olhabrovarets-attends-63rd-biophysical-society-meeting-in-baltimore/; https://bioukraine.org/news/emergingleader-olha-brovarets-shares-her-us-experience-with-bionity-student-biotech-club/). DrSci Ol’ha O. Brovarets’ sincere thanks for the Scholarship of Verkhovna Rada (Parliament) of Ukraine for the talented young scientists given in 2019 year."

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I do not accept the first sentence of the abstract "Quercetin molecule (3, 3′, 4′, 5, 7-pentahydroxyflvanone, C15H10O7) is

an important flavonoid compound, containing two aromatic A and B rings linked through the C ring containing oxygen and five OH hydroxyl groups attached to the 3, 3′, 4′, 5 and 7 positions. This molecule is found in many foods and plants, and is known to act as a natural drug molecule with a wide range of treatment properties, like an anti-oxidant, anti-toxic etc."

1) Quercetin is not a natural drug! So far it is not proved! The anti-oxidant, anti-toxic effects are known, but their therapeutic treatments are not proper studied.

2) The standard quercetin is the 3, 3′, 4′, 5, 7-pentahydroxyflvanone, if we use a standard numeration. The author's numeration corresponds to rotation of the B ring by 180o around C2-C1' bond in respect to the standard! Their molecule is

3, 5′, 4′, 5, 7-pentahydroxyflvanone (in respect to the standard numeration) and the choice of the calculated molecule corresponds to rotation of the B ring by 180o around C2-C1' bond axis. May be the conformer used by authors is the most stable one according to their previous studies, but this is unknown for the plain reader when he starts to read the paper. This should be mentioned from the begining.

3) The first part of the sentence is a simple tautology and needs to be removed.

4) Why proton transfer? (not H atom transfer). The corresponding polarization is not determined.

The MS is interesting and continues the previous studies of quercetin isomers. This molecule is of great biological and medical importance; it received great attention during recent years. All DFT optimizations of transition states and global minima are well documented including Bader's QTAIM analysis of bond critical points. The topology of the electron density was analyzed, using program package AIM’2000 with all default options and wave functions obtained at the level of theory

used for geometry optimisation. The presence of the (3,-1) bond critical point (BCP), bond path between hydrogen donor and acceptor and positive value of the Laplacian at this BCP (Δρ>0) were considered altogether as criteria for the formation of the H-bond and attractive van der Waals contacts. Thus, the MS is acceptable after minor revision (including abstract improvement).

The main objection concerns the influence of the solvent on predictions of this study. There are no comments on this important practical question. In page 6 we have: "All calculations were performed for the tautomeric transitions of the quercetin molecule as their intrinsic property, that is adequate for modeling of the processes occurring in real systems".

Calculations of quercetin in vacuum? with proton transfer? This is not a real system. At least, some comments are necessary.

There are some typos. Even in the first sentence of the abstract one reads"pentahydroxyflvanone"? Thus, the careful reading would be useful.

Reviewer #2: The manuscript by Brovarets’ and Hovorun addresses several intramolecular proton transfer pathways in the quercetin molecule. The authors also examined the properties of the transition states related to these transfers. The employed methods are sound and the results can be reproduced. The authors treated the literature correctly. Yet, they should avoid overcitation of their previous work not related to quercetin. In my opinion, the results of this study are not significant to the broader readership of the Journal since possible biological and chemical roles of the examined pathways are not discussed. The manuscript is not well-written and I suggest a revision of the manuscript.

Additional comments:

Page 2, the sentence “It has attracted a lot of attention last time, due to the wide range of its treatment properties, …” should be modified.

Page 4, DNA bases are not related to their work and references 42-66 might be excluded from the manuscript

Page 4, this text is not particularly important for the presented work: “This points on the fact that proton transfer defines the quantum nature of the biological objects, so-called field of quantum biology, which was started as a separate discipline from late 1920s, when Niels Bohr, delivered an influential lecture on whether the “atomic theory” could help to solve the mystery of life.”

Page 9, “inramolecular proton”

Page 10, “in factthis”

Figure 1, middle panel “hydoxyl”

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Reviewer #1: Yes: Boris F. Minaev

Reviewer #2: No

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Intramolecular tautomerization of the quercetin molecule due to the proton transfer: QM computational study

PONE-D-19-25268R1

Dear Dr. Hovorun,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

Dennis Salahub

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: As far as solvent account concens you refer to future elaboration. I should prefer to write short comment in your present version about limitation of the used vacuum approach.

This is optional deal.

Reviewer #2: I am satisfied with the corrections and thus recommend the manuscript for the publication in the present form.

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Reviewer #1: Yes: Boris F. Minaev

Reviewer #2: No