First revision, 26 May 2021

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(Links below will open the PDF with the Google Docs viewer. Default GitHub behavior would be to download the file instead.)

Article file diff, using latexdiff
revised_manuscript_marked_up.pdf

Response to reviewers
response-to-reviewers.pdf

Cover letter to the editor, to accompany the first revision, submitted 26 May 2021:
Cover_letter_to_the_editor.pdf

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Request for information, 8 July 2021

Some issues were raised by Referees #1 and # 3, and our editorial team would like to discuss them with you before making a decision on the paper.

Referee # 1 is overall happy with the revision, but they are still confused about the audience of the paper. We certainly understand that your target audience is composed of researchers who work in the intersection between software development and research application, but we also understand this reviewer's concern, in the sense that it would probably be a good idea to make sure that both audiences (software development and research application) are covered. Therefore, we decided to discuss this issue in more detail with this reviewer, who suggested that another example calculation could be provided for the computational biophysics readers, such as the change in the binding with respect to salt or pH (linkage analysis), the influence of mutation on binding, or examination of titration state changes. Is this something you would be willing to do? Would this be feasible? This reviewer also mentioned that there are some PB benchmarks for ligand binding energies, small molecule
solvation, etc. that could be used instead, if this makes more sense.

Referee # 3 suggests additional validation experiments (some related to convergence) to be performed to better compare the approach against MIBPB, and we were wondering if it would be feasible to perform these experiments.

You can find both reviews appended to this email. Could you please send me an e-mail that delineates in a point-by-point fashion how you would rectify these concerns if given the opportunity to revise your manuscript? This will help us as editors to make a more informed decision on your manuscript. Please respond to our comments above and to the reviewers' concerns below in a point-by-point fashion.

If there are requests that you feel are inappropriate or would require unreasonable experimental effort to address, please fully explain your arguments.

This information is intended for the editors but be sure to provide sufficient detail for us to adequately assess it. If we decide we would like to send any portion of the response to a reviewer we will first request permission and allow you to rephrase your response.

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Reviewers' Comments:

Reviewer # 1:
Remarks to the Author:
I think very highly of the authors' work and their attention to software (and reproducibility) is excellent--both in past work and in this paper.

The authors have done an adequate job addressing my concerns and the additions in response to the other reviewers' comments are also adequate. It still seems like the paper falls in the limbo between a computational biophysics and scientific computing audience. This is more of a concern for the editor than this reviewer: I am unsure whether to focus my comments on a computational biophysics reader's concerns (MM-PBSA should not be used to compute solvation energies of viruses) or scientific computing reader's concerns (more detailed analysis of scaling, convergence, etc.).

In summary, this paper is publishable as-is although I remain confused about the audience.

Reviewer # 3:
Remarks to the Author:

In Table 6, why are the computational domains chosen as cubics for all proteins for APBS? It is unfair for APBS in terms of efficiency.

In Table 7, solvation free energy comparison shows very large differences (i.e., up to 1.9%) between MIBPB and the proposed method for some molecules. This is a series problem. The convergence of MIBPB is known in the literature (see for example: Nguyen et al. "Accurate, robust, and reliable calculations of Poisson–Boltzmann binding energies." Journal of computational chemistry 38.13 (2017): 941-948.). As shown in Figure 3 of this reference, the averaged relative absolute error of the electrostatic solvation free energies for all the 153 molecules with mesh size refinements from 1.1 to 0.2 ̊A is under 0.3%. I suggest the authors to carry out the same calculations at Nguyen et al. to find out the averaged relative absolute errors of the present method and plot them against those of MIBPB. Please report the numbers of elements at all resolutions.

As noticed by Fenley and coworkers (Influence of Grid Spacing in Poisson-Boltzmann Equation Binding Energy Estimation, J Chem Theory Comput. 2013 August 13; 9(8): 3677–3685), the calculations of Poisson–Boltzmann binding energies is a challenging task. The authors need to produce reliable Poisson–Boltzmann binding energies as shown by Nguyen et al. (see Figure 6 of the above-mentioned JCC reference) for the challenging task proposed Fenley and coworkers. This test will reveal the level of performance of the present method.

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Reply sent to the editor on 12 July.

From the editor, 31 July:

I discussed your paper with our editorial team yesterday. We think that your responses to the reviewers do make sense. Regarding Reviewer # 1’s concerns, we understand that the additional experiments could simply result in a different paper, and that the focus of your current paper is not to introduce a new method, but to provide a usable, reproducible resource to the community that take less computational resources overall.

While your response to Reviewer # 3’s concerns also makes sense, it requires more knowledge in the field; such expertise is unfortunately lacking in our editorial team. Therefore, we would like to share your response to Reviewer # 3’s concerns with this reviewer, and if disagreements are still present, we will make sure to contact our other referees to help us make a decision here.

Therefore, could you do me a favor? Could you generate two PDFs for me, one with your response to Reviewer # 1’s concerns, and another one with your response to Reviewer # 3’s concerns? This will make it easier for us to share with reviewers and also to upload the files in our system for our reference.

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Response sent to the EIC on 2 August 2021

Response to EiC Nature Comp. Sci. and Reviewer 1.pdf

Response to EiC Nature Comp. Sci. and Reviewer #3.pdf