How Symmetry Influences the Dissociation of Protonated Cyclic Peptides

Round 1

Reviewer 1 Report

Manuscript ID: symmetry-1626280

Journal: Symmetry

Review

Special Issue “Asymmetric Molecules and Chiral Recognition”

Title: How symmetry influences the dissociation of protonated cyclic
peptides

Authors: Ariel F. Pérez-Mellor, Riccardo Spezia, Anne Zehnacker

 

This review by A. F. Pérez-Mellor, R. Spezia and A. Zehnacker provides a clear and thorough presentation of the main dissociation mechanisms for a set of protonated cyclic dipeptides, called diketopiperazine (DKP) peptides, that range from symmetrical cyclo-(glycil-glycil) to cyclo-(propyl-tyrosyl) and cyclo-(phenylalanyl-histidyl) where the symmetry of protonation is lacking due to the presence of distinct residues. The relevance of DKP peptides lies in their potential use as shuttles for anti-cancer drugs and as industrial by-products.

In this review, the release of the main neutral fragment (CO) during the collision-induced dissociation is described at a molecular level, relying on chemical dynamics simulations recently reviewed by the authors. The effects of sidechain, symmetry and chirality are carefully examined and discussed offering a timely overview of interest for a wide readership.

It is my opinion that the present manuscript fully deserves to be published in Symmetry.

 

Minor comments:

• For the sake of homogeneity with the rest of the manuscript, change “cyclo-(prolyl-tyrosyl)”

with “cyclo-(prolyl-tyrosyl-propyl)”.

• At the end of p. 4: change “The first step consists in putting the protonated…” with “The first step consists in delivering the protonated…”
• - On p. 9, Figure 7: the Authors should try to present/describe more clearly the results displayed in this figure.
• On p. 11: the title in reference 17 needs to be amended (use of capitol letters).

Author Response

Reviewer 1

Minor comments:

• For the sake of homogeneity with the rest of the manuscript, change “cyclo-(prolyl-tyrosyl)”

with “cyclo-(prolyl-tyrosyl-propyl)”.

I guess the reviewer means cyclo-( tyrosyl- prolyl), it has been done

• At the end of p. 4: change “The first step consists in putting the protonated…” with “The first step consists in delivering the protonated…”

Thank you for the suggestion, it has been done

• - On p. 9, Figure 7: the Authors should try to present/describe more clearly the results displayed in this figure.

We have rewritten the whole paragraph and given more details. The paragraph is now organized in two parts, first the comparison between the different isomerization processes at play, second the comparison between the different systems.

• On p. 11: the title in reference 17 needs to be amended (use of capitol letters).

Thank you for the suggestion, it has been done

Reviewer 2 Report

The authors presented three cyclic dipeptides with different symmetries and natures of the residues. The cyclo-(glycyl-glycyl) represented a symmetrical system whereas the cyclo-(prolyl-tyrosyl) and cyclo-(phenylalanyl-histidyl) represented asymmetrical systems with residues of different natures. The focus of this paper was to explore how symmetry affects the collision-induced dissociation (CID) of protonated cyclic dipeptides. Fragmentation simulations were performed, modeling the collision-induced dissociation efficiency along different reactive pathways, that were subsequently tested experimentally to confirm their theoretical approach. The authors concluded that the charge dissymmetry brought by the proton location on a side chain is the dominant symmetry factor affecting collision-induced dissociation.

 

Comments:

• It would be beneficial to improve the use of English throught the article as some linking words and phrases are wrongly used and affect the flow of the article
  
  

e.g. repetitions:
The concept was completed when Lord Kelvin named this property “chirality” and Le Bel and van't Hoff proposed the asymmetric carbon, a carbon that is attached to four different types of atoms or groups, as a stereogenic center, i.e. a source of chirality.

e.g. inadequate linking words:

They are important as by-products of sweetener degradation, or, in a more positive way, for potential applications as drugs.

e.g. inadequate phrases:

In this three-stage model, the intermediate state encapsulates all the possible geometries the system visits before fragmentation.

 

• In the Experimental and theoretical methods section, the subsections are both labeled as 1. which should be corrected, and a hierarchy should be introduced (subsections with numbers 2.1., 2.2., etc.). Furthermore, the subsection Collision-induced dissociation is labeled as 1.a. however it is the only subsection in the experimental methods (there is no b) so it would be better to label it as 2.1.1.

 

• The Results and Discussion section headings should be revised and corrected with the right hierarchy (the sections Sidechain effect on primary fragmentation of diketopiperazine peptide, Effect of symmetry and chirality should be subsections of Results and Discussion)

 

• It would be beneficial to add letters in the figures that contain more than one result/picture and refer to them in the caption with (A), (B), etc. rather than top, bottom, left, right for a better understanding to what the author is referring to.

 

• Figure 8. should be moved next to Figure 5. for a better understanding of the CO loss mechanism

• It would be helpful to add a new paragraph or correct the existing one describing more in detail the different symmetries (C_i, C₁, C₂) as well as the folded and extended orientations of the substituents to assure a better understanding of the article.

 

The overall impression of this article is that the paper should be rewritten to allow a better flow and understanding of the results.

Author Response

Reviewer 2

Comments:

• It would be beneficial to improve the use of English throught the article as some linking words and phrases are wrongly used and affect the flow of the article
  
  

e.g. repetitions:
The concept was completed when Lord Kelvin named this property “chirality” and Le Bel and van't Hoff proposed the asymmetric carbon, a carbon that is attached to four different types of atoms or groups, as a stereogenic center, i.e. a source of chirality.

Thank you for mentioning we have rewritten the sentence.

e.g. inadequate linking words:

They are important as by-products of sweetener degradation, or, in a more positive way, for potential applications as drugs.

Thank you for mentioning we have rewritten the sentence.

e.g. inadequate phrases:

In this three-stage model, the intermediate state encapsulates all the possible geometries the system visits before fragmentation.

Thank you for mentioning; we have rewritten the sentence as “all the possible geometries of the systems prior to its fragmentation” 

• In the Experimental and theoretical methodssection, the subsections are both labeled as 1. which should be corrected, and a hierarchy should be introduced (subsections with numbers 2.1., 2.2., etc.). Furthermore, the subsection Collision-induced dissociation is labeled as 1.a. however it is the only subsection in the experimental methods (there is no b) so it would be better to label it as 2.1.1.

Thank you for the suggestion, it has been done 

• The Results and Discussionsection headings should be revised and corrected with the right hierarchy (the sections Sidechain effect on primary fragmentation of diketopiperazine peptide, Effect of symmetry and chirality should be subsections of Results and Discussion)

Thank you for the suggestion, we have done the suggested modification.

• It would be beneficial to add letters in the figures that contain more than one result/picture and refer to them in the caption with (A), (B), etc. rather than top, bottom, left, right for a better understanding to what the author is referring to.

Thank you for the suggestion, we have done the suggested modification.

• Figure 8.should be moved next to Figure 5. for a better understanding of the CO loss mechanism.

We prefer to keep it as it is because Figure 8 is deduced from the theoretical results described in Sections 3b and 3c. However, we have added a sentence and referred to Figure 5 at the end of Section 3b for the sake of clarity.

• It would be helpful to add a new paragraph or correct the existing one describing more in detail the different symmetries (C_i, C₁, C₂) as well as the foldedand extended orientations of the substituents to assure a better understanding of the article.

We have considerably modified this paragraph and given more explanations. We have also moved Figure 4, which shows the structure of the studied molecules to facilitate the reading. This figure now is Figure 3.

The overall impression of this article is that the paper should be rewritten to allow a better flow and understanding of the results.

We have rewritten large sections of the paper and we hope it meets your expectations.

Round 2

Reviewer 2 Report

The specific comments were addressed, however the re-written ("We have rewritten large sections of the paper") sections were not highlighted and therefore are difficult to find. It seems that the rest of the text was not changed / improved since the first version. Nevertheless, the text reads a bit better with the provided changes.