Searching for New Antibacterial Compounds Against Staphylococcus aureus: A Computational Study on the Binding Between FtsZ and FtsA
, Armando Hernández-Mendoza 1 and Rodrigo Said Razo-Hernández 1,*Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsComments for Authors:
The study investigates novel approaches using molecular dynamics design to identify inhibitors to proteins that are essential in the binary fission of S. aureus. The docking study found a close correlation with the referenced experimental data and identified two potential PPBI molecules (PPBI 2 and 3) to inhibit the proteins in S. aureus, referred to as SaFtsZ and SaFtsA complexes in the manuscript.
The manuscript is well written, the modeling was thoroughly conducted. However, there are too many assumptions without experimental validation, especially regarding the replacement of the SaFtsZ protein with a short (23 aa) peptide and its mutated version.
Also, more details should be added to the Methods section regarding the MD design:
1. How was the model built? Was a solvated system generated in an e.g., orthorhombic simulation box? What was the absolute distance? How was the system neutralized?
2. What was the force field, force field, temperature and pressure and for how long? What was the recording frequency, and the number of frames in total?
3. How was the hydrophobicity analysis conducted?
4. On Page 3, the Authors state that building the model with I-Tasser yielded disordered structures, leading to using a shorter fragment of 23 aa (316-339) and its mutated versions for SaFTsZ. Could this change cause a bias in the binding between SaFtsA and SaFtsZ in the docking results? The modeled 23-residue peptide and its mutated version seem to exhibit very different binding – are these results valid?
5. On Page 10, the names of the mutated peptides for SaFTsZ are listed: PF23-D372A, PF23-I373A, PF23-P374A, PF23- 271 F376A, and PF23-I377A respectively. However, only the favored poses (PF23-D372A, PF23-I373A, PF23-P374A) are displayed in Figure 10 and Table 6. Explanation is needed why these three are the favored ones.
6. There seems to be a significant difference in binding to SaFTsA between the Fig. 9 (non-mutated peptides) and Fig. 10 (mutated peptide) results.
7. As the crystal structure of the C-terminal tail of the protein SaFtsZ is not available, the Authors could rely only on a hypothetical structure in their model. The modeling was supported by references, no experiments by the Authors were conducted to validate the model. Would it be possible to test the effect of the 23 aa peptides and their mutated versions on S. aureus duplication?
Minor Comments:
1. The title includes FtsZ and FtsA, however, in the manuscript all over SaFtsZ and SaFtsA are used. This is somewhat inconsistent.
2. Please explain abbreviations, for example, for “RMSD” (the measure of the difference between the ligand crystal conformation and the prediction of docking).
3. Should the caption “peptide form PepFold23” be “peptide from PepFold23”?
4. In Table 4, should “Complejo SaFtsA-“ be “Complete SaFtsA-?
Comments on the Quality of English LanguageEnglish language is fine, only few minor typos noticed.
Author Response
The responses to the reviewer comments are displayed in the file named "Editor and Reviewer comments_DDC_reviewer1" which is attached below.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsDear authors,
Please, review all figures. Some of them, as figure 1A, 1B,figure 2 and 6 are missing in the manuscript. Same when you do not mention figures in the main text and then these figures appear.
Important: Which are the chemical structures of PPBI1, PPB1 and PPBI2?? You mix these stuctures, for example in figure 14 and 15 PPBI2 show different structures!!
Comments on the Quality of English LanguageFine
Author Response
The responses to the reviewer comments are displayed in the file named "Editor and Reviewer comments_DDC_reviewer2" attached below.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsThis Reviewer would like to thank the Authors for thoroughly addressing the review comments.
