Wednesday, May 16, 2012

Reviews of the first PLoS ONE paper

The review of the PLoS ONE paper we submitted February 23 came back April 26th and can be found below.  Too slow, PLoS ONE!  One the other hand I have been so swamped with teaching, I didn't have a chance to really look at them until now.

My first reaction based on a quick read-through back in April was "nothing we can't handle".  My second reaction comes here, and deals with the points raised with reviewer 2.

1. The calculations with diffuse functions are running.  The main problem will be getting FMO2 results for comparison (due to likely convergence issue), but we can hardly be faulted for that.

2. We can clarify that.

3. "chemically reasonable and sufficiently separated fragmentation points".  Also we should add references to the paper on FMO fragmentation in zeolites.

4. I think we'll have to re-look at the raw data to see if we can come up with a better analysis.  As I remember the errors seemed pretty random (which is supported by the low average error) and it was hard to pin it to any structural feature.  Also, FMO single points with PCM for P3 that show the error might be good.

5. The sentence in the covalent bond section should be removed.

6. The largest errors for the EFMO and FMO2 results listed in Table 1 are 26.23 and 25.59 kcal/mol, respectively.  I would call that similar "magnitude".

7. Oops.  We should fix that.

8. We should add "With the exception of the RHF EFMO results, the errors are roughly additive for the poly-alanine peptides, so the error is discussed on an per residue basis" and we should change 0.00 to < 0.01 kcal/mol.

9. We should add labelled arrows pointing to those residues

10. We should fix that

11. We should fix that

12. If I remember right, this lead to quite large errors in the energy (we should check).  If so we should note this, perhaps as a supplementary table.

13. We should fix that

14. We should fix that


________________________________________
From: em.pone.0.2aabee.023d82b1@editorialmanager.com [em.pone.0.2aabee.023d82b1@editorialmanager.com] on behalf of PLoS ONE [plosone@plos.org]
Sent: Thursday, April 26, 2012 4:16 PM
To: Casper Steinmann Svendsen
Subject: PLoS ONE Decision: Revise [PONE-D-12-06195]

PONE-D-12-06195
The Effective Fragment Molecular Orbital Method for Fragments Connected by Covalent Bonds
PLoS ONE

Dear Mr Steinmann,

Thank you for submitting your manuscript to PLoS ONE. After careful consideration, we feel that it has merit, but is not suitable for publication as it currently stands. Therefore, my decision is "Major Revision."

While one reviewer is generally positive about your submission, the second one raises a number of important points that you should deal with in detail. We invite you to submit a revised version of the manuscript that addresses these points and encourage you to submit your revision within sixty days of the date of this decision.

When your files are ready, please submit your revision by logging on to http://pone.edmgr.com/ and following the Submissions Needing Revision link. Do not submit a revised manuscript as a new submission.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

Please also include a rebuttal letter that responds to each point brought up by the academic editor and reviewer(s). This letter should be uploaded as a Response to Reviewers file.

In addition, please provide a marked-up copy of the changes made from the previous article file as a Manuscript with Tracked Changes file. This can be done using 'track changes' in programs such as MS Word and/or highlighting any changes in the new document.

If you choose not to submit a revision, please notify us.

Yours sincerely,

xxx (name removed upon request)
Academic Editor
PLoS ONE

Reviewers' comments:

Reviewer #1: although the topic of this ms is relatively too specific, the authors have presented an efficient computational method for fast and accurate calculation of total energy and gradient of large molecules. This method improved their previously developed technique lots, e.g covalent bond and speed. I would sugguest to accept it for publication.



Reviewer #2: Manuscript title: The Effective Fragment Molecular Orbital Method for Fragments Connected by Covalent Bonds
Corresponding Author: Casper Steinmann

The manuscript describes improvement of the EFMO method developed by the authors. The EFMO after this modification is able to describe the molecular fragments with covalent bond to neighboring fragment. This is quite significant improvement of the EFMO method. The new method was tested on several protein-like models and small proteins and observed results were compared to other known FMO method and full HF and MP2 approach. The major advantage of the EFMO method is calculation speed up compare to the FMO2 and full HF and MP2 calculations. On the other hand, in some cases EFMO method generates quite significantly higher  energy errors compared to other mentioned methods.

Comments:
1.      Almost all calculation were performed using the 6-31G(d) basis set. However, benchmark with water cluster (Table 3) shows significant error lowering using the diffuse functions (change of the basis to 6-31+G(d)). It would be interesting to see, whether such change could significantly lower also observed errors (Table 1) for the protein-like models or small proteins.
2.      In section Theoretical Background: For lucidity, authors should specify more precisely, by what kind of process are "EFP parameters (...) derived on-the-fly completely automatically".
3.      In section Computational Methodology: In "Covalent Bonds" subsection (page 3), authors claim, that "given any chemically reasonable fragmentation points, this theory is transferable to other systems (than proteins)". However, in this subsection (Computational methodology), authors discuss only two residues per fragment fragmentation, "because of the large charge transfer in some charged systems the one residue per fragment division leads to very considerable errors." Authors should explain this behavior compared to claim written in previous paragraphs.
4.      In paragraph dedicated to polypeptides benchmark discus observed high errors for the peptides with charged amino acids. Authors observed quite high errors for the polypeptides with two or four charged amino acids. Errors are 2x (two charged AA) or 3x (4 charged AA) higher as for the neutral polypeptide. Authors should discus also this observation, if it is some systematic error of the method or it is only specific for the studied polypeptide and not only say, that water screening might lower observed error. Authors state that EFMO method should be used on the proteins, which are in many cases highly charged, so I think that this behavior of the method should be investigated deeper.
5.      In section Application to Polypeptides: Authors set the screening parameter alpha to 0.1. However, in Covalent Bonds section, they inform reader about "investigating the need to change screening parameters since...". Reader would expect broader discussion about tuning screening parameters for calculations for other systems of potential interest.
6.      The authors state on page 8 row 5: "EFMO shows errors of similar magnitude to FMO2/AFO." On the base of the data listed in Table 1 I can't agree with it. In some cases is the error produced by the EFMO higher by 4 - 12 kcal/mol compare to the FMO2 and this is not the same magnitude.
7.      In the first and second paragraph on page 8 are several incorrect values of energy errors, which do not correspond to the values in the Table 1. Authors should carefully recheck these values.
8.      The authors divide the observed errors in energy by the number of alanine residues. Does it means, that error is cumulative and for the (ALA)100 should be 10x higher as for the (ALA)10? Other issue is that in case of the (ALA)40 authors divide energy error (0.18 kcal/mol) by the 40 and write that error per residuum is 0.00 kcal/mol. What is not true (0.18 / 40 = 0.0045), because in such case should be error for whole (ALA)40 also 0.00 kcal/mol (0.00 x 40 = 0.00). In my opinion is better to write something like "error is lower than 0.01 kcal/mol".
9.      The authors on page 9 discus some errors on specific atoms from Figure 6. However, these atoms are hardly seen on the Figure 6. In my opinion, if these atoms are discussed they should be somehow marked in the figure.
10.     Atom 155 is described as backbone carboxylate. I think it is not correct, if it is CO on protein backbone it is backbone carbonyl.
11.     In section Molecular Clusters: For better lucidity, authors should refer values mentioned in this subsection to data in appropriate Table.
12.     In section Timings: Authors note, that significant speedup may be achieved by lowering cutoff distances Rresdim and Rcorsd. However, the values of cutoff distances may be crucial for the calculation accuracy. Authors should deeply discuss, how the cutoff values of Rresdim and Rcorsd affect the accuracy of calculation and not only overall timing.
13.     The plot labels on Figures 4 and 5 are misleading in my opinion. Plots represent the MAD or Avg. Dev. Between two methods M and X, where M is FMO2/HOP, FMO2/AFO or EFMO and X is RHF or MP2. So the labels should look like FMO2/HOP-RHF and not FMO2-RHF/HOP, because it evokes that it is difference between FMO2 and some RHF/HOP method.
14.     Table 2 title should include also the description of the abbreviated methods.

In my comments, I omitted notes about the typos because I think that it is author's responsibility to check the spelling of the text. Generally, the work described in the manuscript is interesting and might be useful for specialized computational chemists. I therefore suggest  authors to consider publishing their manuscript in more specialized journal like J. Phys. Chem. A. after the incorporation of the above comments.

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