Computational Insights into the Interaction between Cytoadherence Receptor gC1qR and the DBLβ12 Domain of a Plasmodium falciparum PfEMP1 Ligand

Round 1

Reviewer 1 Report

Comments

The paper has novel insights in malarial research, I appreciated all the authors for there efforts. There are many major concerns to be addressed:

1. The PatchDock used for the work is in-sufficient to carry docking experiments. The server is providing lot of errors on the 3D structure. I recommend the authors to perform docking studies using any other valid commercial or non-commercial softwares like AutoDock, Schrodinger, etc.
2. I also suggest multiple-docking validations are needed incase of using online docking servers like Patchdock (1click dock server, HADDOCK, DockingServer etc).
3. Why authors chosen multi-templates for modelling, as the entire sequence was covered in the PDB retrieved crystal structures of DBLβ12 domain.
4. Why authors selected a structures with and without complex for modelling. Is there a reason behind?
5. 87% and 89% of stereochemical property shows the model generated is not reliable. In such case authors has to mention whether the active region or the region identified in the current study is located outside the allowed region or not. I suggest mentioning this point in results section to justify Figure 3. along with good number of references eg: PMID: 34278137.
6. Mention the grid size used to perform docking studies to uncover residues lying from 700 to 1100 where the binding region exists.
7. Does the active site residues identified in the study are unique and parasite specific? If yes or no mention in discussion.
8. Increase the quality of figures to make them more legible.
9. Authors need to perform MD simulations for 100ns to know the stability and to enhance the insights of the work.

The work is worth publishing in the reputed journal after the modifications suggested

Good Luck !!

Author Response

Please see the attachment 

Author Response File: Author Response.docx

Reviewer 2 Report

The authors studied the binding of DBLβ12 domain of PfEMP1 with the human receptor gC1qR using computational methods.

- Since the importance of the protein-protein docking method to this study, I would suggest them to add supplement representations of the 3D molecular structure of DBLβ12 domain and gC1qR, and the protein-protein complexes. Tools such as PDBePISA can be helpful to the authors for the calculations of macromolecular interfaces.

- My main concern is about Fig. 4. The authors claim that some bonds are stronger than others but it is not completely clear to me how they quantify it. How do the authors calculate this strength? Fig. 4 is not adding anything more than Table 2, apart from the strength of the interactions but they seem quite arbitrary. Also, is it known which atoms of the residues are interacting? I suggest to rethink the whole figure and the messages the authors would like to convene, which in my opinion are two: 1. the type of bonds and their strength. 

Further minor corrections:

• Labels for helix in Fig. 2A are missing
• Row 187: the solution face is the only face for binding
• Check sentences rows 245-247 and rows 252-253 (verb is missing)
• Row 330: P. falciparum infected erythrocytes bind to cell surface
• Row 335 no comma

Author Response

Please see the attachment

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

The manuscript is accepted from my side now, all comments are responded well. 

Good Luck !!