Wednesday, June 27, 2012

Bill for Casper's first PLoS ONE paper

It's time to pay the #openaccess piper: the bill for Casper's first PLoS ONE paper.  The don't exactly waive their fee waiver option in your face, do they?  Still not clear how one would ask for one, other than replying to the email.  Anyway, I have the dough for this one so I sent the bill on to our administrative unit .... along with all our empty bottles from the Xmas party.

Dear Author,

Thank you for choosing to publish with PLoS - by now you will have received an email confirmation that your article "The Effective Fragment Molecular Orbital Method for Fragments Connected by Covalent Bonds" PONE-D-12-06195 has been accepted for publication. Therefore, please find appended an invoice PAB48066 for this article.

Thank you for publishing with PLoS and congratulations on your upcoming publication!


Author Billing Team

Public Library of Science

Reviews of Casper's second PLoS ONE submission

The reviews for Casper's second PLoS ONE submission, submitted around May 25th are in.  Let it not be said that all #openaccess papers are carelessly reviewed!

I have all but skimmed it but the only major concern of Reviewer #1 is of course very easily dealt with (good point by the way!).

Similarly, the major criticism of Reviewer #2 is also easily dealt with.  We were of course aware of the FMOUtil program, but I am not sure what a comparison would entail?  We should of course point out any differences in the input files produced by FragIt and FMOUtil for polypeptides and emphasize the advantage of FragIt (general applicability) by doing a few more examples like DNA and perhaps a large ligand bound to a protein?

FragIt: A Tool to Prepare Input Files for Fragment Based Quantum Chemical Calculations

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."

We invite you to submit a revised version of the manuscript that addresses all the critical points raised by both reviewers.

We encourage you to submit your revision within sixty days of the date of this decision.

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Yours sincerely,

 xxx (name removed upon request)
Academic Editor

Reviewers' comments:

Reviewer #1: Review of FragIt: A Tool to Prepare Input Files for Fragment Based Quantum Chemical Calculations

Steinmann et al. present a description of FragIt, a command-line program to prepare GAMESS input files for Fragment Molecular Orbital Calculations. Fragments are generated by bond cleavage at bonds that match particular SMARTS patterns, which simplifies the procedure in particular for polymers such as proteins and oligosaccharides. As the authors point out, without a tool of this sort, it would be next to impossible to prepare input files for any but the smallest proteins.

The manuscript is overall clear and well-written, but could have benefited from a final careful edit before submission as there are many trivial issues. I tested out the software, and it worked without problems (thank you for including a test file).

(1) This paper does not describe a particular version of the software. Please make a version 1.0 release available from the Github download site or elsewhere. Given that most computational chemists may not be familiar with Github, please provide a simple download link for the software to be downloaded.

(1) Spellings: Copenahgen, dilengtly, indepth, chargetransfer, "rise to further" not "rise further", "in Figure" not "on Figure", "nescessary", "input file for" not "input file to", "because we" not "because of we", "aswell", "supplimentary"
(2) Page 1, line 52: Please describe what is behind the "etc". (I would like to know)
(3) Is this tool only specific to proteins and oligosaccharides? Can you make this clearer? The MMFF94 forcefield only supports a limited subset of atom types, and already in the introduction at page 1, line 52, you start talking about proteins. If this is the case, perhaps you should also mention this in the title.
(4) This tool appears to be specific to GAMESS. While I would encourage you to develop your software in such a way that it could be used for other comp chem packages, if that is not your goal, perhaps you should name GAMESS specifically in the title, i.e. A Tool to Prepare GAMESS Input Files. Otherwise you may mislead or disappoint the reader, and in this way you also highlight it to GAMESS users.
(5) Colloquialisms: "doable", "mean feat", "we've", "don't". While I have no particular problem with the use of these, such expressions are not generally found in the literature and may be confusing to non-native speakers (who form the majority of the readership).
(6) The figure numbers correspond to the legends, but not the actual figures in the PDF provided. Naturally, this caused me some confusion.
(7) I found it unusual that the Results section preceded the description of the software and dataset. In fact, I skipped reading the Results until the end, and I would recommend you consider rearranging the manuscript accordingly.
(8) Is there software available already which can already perform the same action? This wasn't very clear to me. For example, you reference Open Babel on Page 2 but Open Babel has no particular abilities to prepare FMO files.
(9) As someone who is not familiar with FMO calculations, I would have been interested to read a general description of why they useful, how fragments should be decided, what is the associated decrease in accuracy, the increase in speed, and so forth. Perhaps the authors could consider a paragraph on this as this feeds into why the software is important.
(10) EFMO is mentioned on Page 2, line 33, but not again in the paper. Is this supported or not (and how does it differ)?
(11) Abbreviations such as FMO, EFMO, SMARTS should be listed with capitals, e.g. "Fragment Molecular Orbital" not "fragment molecular orbital"
(12) Page 5, line 39: Remove line referencing Pybel if not used.
(13) Page 5, Line 53: Here it says that "explicitly defined valid pairs of atoms" can be used instead of substructure patterns, but elsewhere in the manuscript there is no example of this. Could the authors provide an example of usage?
(14) Page 6, line 10: do you mean "combines two or more adjacent fragments?" (subsequent means neighbouring in time)
(15) Page 6, line 33: What does FMO/FD stand for?
(16) Page 6, line 37: This sentence is confusing. How about "One defines a central fragment as above and a distance. Fragments which have atoms with this distance..."
(17) Page 8, line 26: "--output-active-atoms" not "--output-active-distance" according to the version of the software I downloaded.
(18) Please add a section in the manuscript describing the contents of the Sumpplementary Section.
(19) References. Reference formatting is not consistent. SOmetimes journal titles abbreviated, sometimes not. Should be Avogadro in Ref 9 not Open Babel. All titles are in lowercase even though this may be incorrect (e.g. ref 8).
(20) Figures. Which are the active, inactive and frozen regions in Figure 6?
(21) Consider including a LICENSE.txt with the source code. This makes the license more obvious.

Reviewer #2: The manuscript describes FragIt, a novel and flexible method and corresponding
software package to prepare input data for quantum chemical calculations using
fragmentation methods (the FMO method in particular).  The presented results
are rather narrow in focus (FMO method of the GAMESS package for polypeptides
and polysaccharides), but generally applicable and easily extensible in theory.

The described software is open source and builds on other cheminformatics
software (Open Babel and PDB2PQR).  It is written in python which makes it
easily usable and modifyable by most computational chemists.  Due to the use of
SMARTS patterns which can be specified at run-time, no software engineering is
needed to apply FragIt to different systems.

Our main criticism is the lack of comparison with the available FMOUtil package
(see general comment 4 below).  This point must be addressed before
publication in our opinion.

Less important but still higly recommended for consideration are our general
comments 1, 2, 3 and 5 about the abstract/introduction - we think some
rewriting would add to the clarity of the manuscript.

As such we recommend to accept this manuscript for publication provided the
above points (general comments 1-5) have been addressed and the other points
considered (unless they indicate clear mistakes).

General comments:

1. The beginning of the introduction mentions fragmentation methods in general
but lacks a clear statement about which method they support in particular.
From the rest of the manuscript, it appears that FragIt is (for now) specific
to Kitaura's and Fedorov's FMO method as implemented in GAMESS. As such, it
would appear appropriate to quickly summarize the method and its main features
to the PLOS One readership.

2. The second part of the introduction discusses the "tedious tasks" one has to
undertake to setup program packages for fragmentation methods and mentions some
prior software which "can perform some of these tasks".  However, these tasks
are not presented at this point (they appear to be implicitly presented by
explaining the work-flow and fragmentation algorithm later on).  While a
thorough discussion of them should be left for later sections, we think it
would add to the manuscript to present them in the introduction.

3. The discussion of prior software packages with similar scope is lacking.  The
authors cite Avogadro, Open Babel and Facio.  Avogadro is a molecular modelling
application with support for GAMESS input deck generation, but (to our
knowledge) not including fragmentation.  Open Babel is a general cheminformatics
toolkit and has (to our knowledge) no special features targetted at
fragmentation methods besides the SMARTS handling the authors are using in
FragIt.  Facio appears to be a general-purpose molecular-modelling
application includings GAMESS input file / visualization support.  The
screenshot at implies it includes support
for the FMO method, so the authors should discuss which tasks (see above point
2) Facio is unable (or only poorly/difficully able) to perform compared to

Further, PEACH ( is a
related link, the main link appears to be gone) appears to be able to fragment
DNA and dump GAMESS output (besides ABINIT output), but its availability and
usage is unclear to us and has not been evaluated.  Nevertheless, it should
probably be mentioned along the others as well.

4. In addition to the above general comment 3, the authors completely ommitted
FMOUtil (, written by the
authors of the FMO method itself.  It appears to be the most obvious choice for
comparison: it is similarly licensed as FragIt (GPL version 2, according to the
source file and program output) and of similar usage (command-line tool dumping
a GAMESS input file), albeit of more limited scope (restricted to
proteins/polypeptides).  An additional feature of FMOUil appear to be grouping
of glycine residues to the previous fragment, the authors could address why this
is not done in FragIt and/or add this if easily implemented via SMARTS.

As most of the results are about polypeptides, we would even advise to include
FMOUtil fragmentation results for comparison in the results sections, rerunning
the fragmentation with FMOUtil should not take long.

5. In the light of general comment 4, the unique advantages of FragIt are not
very prominently mentioned.  The authors supply patterns for polypeptides and
polysaccharides.  Due to the residue-centric PDB format, fragmenting proteins by
residue appears to be a simple problem, while polysaccharides are probably a
very less common target for quantum chemistry applications in need of
fragmentation methods.  The unique advantages compared to e.g. FMOUtil appear to
be (i) the possibility to fragment peptides at different bonds along the
backbone than what is indicated in the PDB file and (ii) to easily fragment
arbitrary other types of polymers without the need to change the source code or
otherwise difficult setups.  Point (ii) is only indirectly addressed on page
7/line 55 in a comment on testing new pattern.

As such it would make a stronger case for FragIt if further patterns for other
types of polymers (the most notable example would be nucleotides) were
presented or at least their easy development stressed more.  The last section
(Availability and Future Directions) mentions DNA (page 9/line 5), but at the
very end of the manuscript, and only one more example (solid state systems) is
mentioned, which underplays the apparent versatility of the SMARTS approach in
FragIt in our opinion.

Rewriting parts of the abstract to this end should be considered as well.

6. The grouping of the sections is unusual: the results are presented before
the Design and Implementation.  From reading the manuscript, one gets the
feeling it has originally been written the other way around, e.g. the PDB codes
are only mentioned at the very end when the dataset is described, not on the
first mention of the respective proteins and the figures 2-4 are mostly generic
figures whose referencing in the Results section looks slightly misplaced.

7. The results are strictly limited to the fragmentation and their respective
merits are discussed without backing from QM calculations.  While full-scale QM
calculations would likely be out-of-scope for the manuscript, a more thorough
discussion (possibly with references to quantitative comparisons) about which
fragmentation results are desirable in general would useful in order to better
assess the various FragIt options.  The authors refer to references 21 and 22
with respect to the fragementation of peptide bonds, but fragmentation sizes
etc. are not discussed that much.

8. The terms of the availability (especially the software license) are not
clearly stated in the Availability and Future Directions section.  According to
the code on github, FragIt is licensed under the GPL, version 2 (or later); we
believe it should at least be mentioned that it is distributed under an open
source license.  We would also suggest to include a (web-)citation for the
FragIt code for indexing and linking purposes instead of the single inline URL
on page 8/line 53.

9. Although the FMO-specific parts of the generated GAMESS input is the crucial
part of FragIt, it seems to write a complete GAMESS output including hardcoded
default settings for the ab initio method and basis sets.  Those
non-fragmentation specific parts of the input are probably supposed to be edited
by the user to their needs.  FMOUtil (see general comment 4) apparently includes
support for various methods and basis sets implementing the FMO method, so
discussing the nature of the default SYSTEM/SCF/CONTROL/BASIS groups in the
Writing the Input Files section should be considered.

10. The section Availability and Future Directions could discuss possible
interaction or inclusion of FragIt in other (open-source) software packages, the
most likely being Avogadro (reference 9), which already includes a sophisticated
GAMESS input deck generator and a plugin infrastructure including python
support.  Avogadro being a graphical application might eben make it possible to
interactively manipulate fragment boundaries.

11. The paper is sometimes written in a somewhat informal style (see e.g.
page 2/line 15/16, "is [...] no minor task when you have hundreds of fragments")
and we encountered several language issues or errors that we have not explicitly

Specific comments:

Page 1, Line 39: we suggest adding a citation to the recent Chem. Rev. review
(DOI: 10.1021/cr200093j) of fragmentations methods to the end of the sentence
"[...] such as fragmentation methods".

Page 1, Line 48: the pointer to the supporting information regarding the
complexitiy of input files for fragmentation methods compared to conventional
methods seems unnecessary here.  First off, there are numerous fragmentation
methods and some might not require much more complex setup than conventional
ones.  Further, the supporting information does not appear to contain any
conventional input files for comparison anyway.

Page 2, Line 37: PDB2PQR is not only available online, it can be freely
downloaded and installed locally for (offline) use with FragIt.

Page 2, Line 38: the reference to the RECAP algorithm without further
explanation looks misplaced in the introduction and could be moved to the Design
and Implementation section.

Page 3, Lines 14-22: the usefulness of the molecular cluster example is unclear.
If the only reason for its inclusion is to show FragIt will fragment seperate
molecules to one fragment each, this could perhaps be folded into the Design and
Implementation section.  The specific example (16 water molecules and one
tyrosine) leads to 16 very small and one big fragment.  It is unclear how this
is a "good" result considering the size difference of the fragments; if this
results is indeed better than grouping maybe 2-3 water molecules into one
fragment, this should be discussed.  We suggest to omit or move this subsection.

Page 4, Lines 10-19: the description of figure 5 is hard to follow.  Several
fragments in figure 5 have the same color, and the text does not discuss them,
just summarized the fragment size.  It would be clearer if the text would
mention the color and/or fragment number according to the panels in figure 5.
Another possibility would be to enhance the caption of figure 5 to include that

Page 4, Lines 21/23: it is unclear whether the lack of fragmentation along
disulfide bonds "unless a specific pattern is supplied" is intentional (and thus
desired), or simply a missing feature.  Further, the discussed results include
no example with disulfide bonds, while the test set does (see page 7/line 14),
though also without discussion.

Page 6, Line 30: we assume fragement I is the central fragment mentioned before,
it could be mentioned explicitly to make this clearer.

Page 6, Line 44: (web-)citations for PyMOL and Jmol should be provided
(reference 29 cites Jmol, but only later in the manuscript on page 8/line 46).

Page 6, Line 44: "visually inspect" is vague, we assume the output scripts
include markup so that PyMOL/Jmol will color each fragment differently (as
shown in the figures), this could be mentioned more specifically (perhaps
referencing one of the figures), including possible other features.

Page 7, Line 26: (web-)citation for NumPy could be provided considering Python
got cited earlier in the manuscript as well.

Idem: The strict dependency on Python 2.6 is not explained; if this was indeed
the case, it would seriously narrow the field of use.  Another possibility is
that the "(or greater)" after Numpy applies to Python as well, in this case this
should be made clearer.  If Python 2.6 is just the version used by the authors,
we suggest adding language like "has been tested/validated with Python 2.6".
The same applies for OpenBabel, the supported version should be mentioned here;
as reference 10 specifies version 2.3.0, this could be mentioned here as well.

Comments on References:

1. Several journals are not abbreviated correctly, e.g. reference 1 (J Comput
Chem), reference 2 (J Chem Theory Comput), reference 11 (J Cheminform) or
reference 27 (Chem Cent J).  We did not check all references for this.

2. Reference 5: the bibliographical data for the book "CRC" is incomplete, it
should be something like "CRC Press, Boca Raton, FL".

3. Reference 9: wrong title, it should probably read "Avogadro v.1.0.3.".

4. Reference 16: the ID for the arXiv preprint is missing a dot, it should be

5. Reference 23: The URL is not marked up like the other URLs in e.g.
references 24-26.

Comments on Figures:

1. The figures are referenced out-of-order in the text in the sequence
1-2-5-3-4-7-6-8.  Further, the captions and uploaded images do not match;
uploaded figure 2 is labelled "algorithm" (figure 7 caption) and every later
figure is offset by one between the uploaded figure and the figure caption due
to this.

2. Figure 1: similar to the results it depicts (see comments to page 3/lines
14-22 above), the usefulness of figure 1 is dubious.  It displays the
water/tyrosine cluster in two panels, with regular atom-coloring in the first
panel and fragment coloring in the second.  However, for the second panel, there
are fewer different colors than there are fragemnts, so several fragments have
the same color.  As the fragments are not otherwise labelled, the actual result
is contradicted, i.e. that every independent molecule is a seperate fragment.
We suggest removing the figure or at least adding labels to the repeatedly
colored fragments and/or clarify the coloring/fragmentation in the caption.

3. Figure 6: the caption should explain the coloring with respect to the
mentioned regions, possibly also denoting the fragment indices so that
the figure can be understood for black-and-white printouts.

4. Figure 7: the caption looks superflouos and unnecessary.

Comments on Tables:

1. Table 2: the comment "d.o." in rows 2-6 is unclear to us - pardon our
ignorance if this is an otherwise common abbreviation.  If it signifies "see
above", "v.s." (vide supra) could be used instead, or just the first comment
"capped with methylene" be repeated.

Comments on Software:

1. No release has been made of FragIt so far, only the git trunk is available.
We advise on releasing a version and tarball in conjunction with the paper for
future reference.  This must not be a 1.0 release.

2. Only version 2.6 of python is supported (the documentation mentions ongoing
work to support further python versions).  As FragIt is not a big project (below
2k lines of code, 25% of which belongs to the test suite), we suggest removing
the python-2.6 dependency for a public release (see software comment 1), if

3. The config file format conflates generic configuration values ("writer", the
default patterns, output options) with specific results for a particular PDB
file ("explicitfragmentpairs" and "explicitprotectatoms").  This might be due to
option parsing, but is non-intuitive.  The same goes for requiring a PDB file
for dumping the configuration values into a file.

4. It is not possible to enable/disable protection patterns via command-line
options (at least according to --help output) the only way to do this seems to
be by changing the config file.  Compared to some of the other command-line
options, this one seems rather important to us so we suggest adding it.

5. Including a (probably trivial) script for installation and
deployment as is customary for python software is advised.

Sunday, June 24, 2012

First PLoS ONE article accepted! (part 2)

So the paper needs some work (TM). All required details are minor and most of it is regarding the SI. Apparently that information has to be in the paper (maybe for easy referencing?) and uploaded as separate files. Oh well, you learn something new everyday.

Edit 1: So the SI was split up into multiple files and submitted individually, legends were added. Now there is a reference to "Text S1" in the manuscript - we'll see how the production staff handles that. It will be interesting.

Below is the complete message I got:

Dear Mr Steinmann,

Re: "The Effective Fragment Molecular Orbital Method for Fragments Connected by Covalent Bonds"

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This work was funded by a Schou Fellowship to JHJ from the Danish research Council. CS was sponsored by the insilico rational engineering of novel enzymes (IRENE). URL:
DF is sponsored by Next Generation Super Computing Project Nanoscience Program (MEXT, Japan) and the Computational Materials Science Initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Tuesday, June 19, 2012

First PLoS ONE article accepted!

Aahh, our first PLoS ONE paper.  Submitted February 23rd - accepted June 19.  Of course it's been freely available on arXiv (and my Google Scholar page) the whole time.

Now for the, ahem, $1350.  You see the thing about that is ... run!

From: [] on behalf of PLoS ONE []
Sent: Tuesday, June 19, 2012 4:11 PM
To: Casper Steinmann Svendsen
Subject: PLoS ONE Decision: Accept [PONE-D-12-06195R1]

The Effective Fragment Molecular Orbital Method for Fragments Connected by Covalent Bonds

Dear Mr Steinmann,

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLoS ONE.

Your manuscript will now be passed on to our Production staff, who will check your files for correct formatting and completeness.  After this review, they may return your manuscript to you so that you can make necessary alterations and upload a final version.

Before uploading, you should check the PDF of your manuscript very closely. THERE IS NO AUTHOR PROOFING. You should therefore consider the corrected files you upload now as equivalent to a production proof. The text you supply at this point will be faithfully represented in your published manuscript exactly as you supply it. This is your last opportunity to correct any errors that are present in your manuscript files.

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Reviewers' comments:

Reviewer #2: The authors performed all changes I required. The paper may be accepted.

[NOTE: If reviewer comments were submitted as an attachment file, they will be accessible only via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

Wednesday, June 13, 2012

Reviews of Martin's 2nd PLoS ONE article

The reviews for Martin's second PLoS ONE paper, which was submitted May 4, came back Monday.

My gut reaction is "Nothing we can't handle".  In particular the quantitive aspect specifically mentioned by the editor as we already have a paper on this.

The most critical change I think is adding 2-3 paragraphs in the introduction that summarizes the model, the assumptions behind it, and its use to interpret the results by us and others (i.e. very briefly summarize the papers who have used the previous BioFET-sim papers or the original paper by Mads Brandbyge and co-workers).  Yes, there are approximations in the method but given the accuracy with which key experimental parameters are known at present for these sensors, more accurate methods are not really warranted.

We also need to be more explicit about the availability of the code as requested by the second reviewer.  Perhaps we should simply make it available on Github and stop messing with the distribution ourselves?

BioFET-SIM Web Interface: Implementation and Two Applications

Dear Prof Hediger,

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."

We invite you to submit a revised version of the manuscript that addresses in particular the important points raised by ref 1 on the quantitative aspects of the results of the web application.

We 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 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

Reviewers' comments:

Reviewer #1: Review of "BioFET-SIM Web Interface: Implementation and Two Applications"

As a true admirer of the web-based computing and simulation through, I can not overstate the importance of web-accessible, easily usable, computational tools for designing and interpreting experiments. Over the years, I have contributed a series of tools and therefore I understand the effort it takes create, document, and distribute such an application. Therefore, I read the paper with significant interest.

I have several questions regarding the physical model that needs to be clarified:

(1) The authors calculate the conformation and charge of proteins by downloading data from PDB and using classical formula for calculating pH-specific charges of the residues. I wonder if the calculations are correct when a metal surface is present that creates an image charge - changes the conformation significantly. I wonder how this effect is accounted for.
(2) Salt screening appears to be included through Sorensen's approach through Eq. 7 (Is this true)? The authors do not describe clearly how the screening model was adapted for this particular application? What are the limitations of the approach?
(3) What about pH-dependent surface charge associated with SiO2 and Al2O3 through site binding theory?
(4) The model for transistor part is exceeding simple. I see that there is no distinction between inversion, depletion, and accumulation modes of operation. Even simple SPICE model could be very useful.
(5) Where is the reference electrode and how is the effect is accounted for in the equations? People often use the reference electrode to bias the transistors and I see no mention of reference electrode in the paper.

Frankly, my feeling is mixed: If I recommend publication, people will have a toy model to give qualitative insights into the biosensing problem. The string of software linked together is also useful - people find it difficult to use them separately. However, the reason I feel uncomfortable recommending the publication is that despite the details giving the appearance of complicated analysis, the results are likely to be quantitatively incorrect. I worry about it particularly because the authors in their work did not project a nuanced understanding of the problem. The authors should consider rereading works by Berg, Manning, Landheer, Nair/Alam, etc. and rewrite the paper to highlight the assumptions, limitations, and the context. Also, a review of existing biosensor simulators in reference to the current model will be useful. I will recommend publication if these revisions are made, references are updated, and assumptions/limitations are clearly hightlighted, .

Reviewer #2: First of all, I have to say that my working field is not at all close to Biosensors, so I'm not doing any comments about the theory behing this web application hopping that other referees will. However, I do work with protein structures and web applications that handle them, so I still feel I can contribute to review this paper.

The manuscript describes a web application devoted to simulate the change of conductance in a nanowire when a biomolecule is bound to it, depending on the orientation of this biomolecule. According to the authors, this process used to require some complex steps that they have reduced to a couple of clicks and a few parameter adjustments, all in a very visual way. The authors also provide two examples. In the first one, they demonstrate how different orientations of the biomolecule on the nanowire influence the final result due to the different positioning of charges. In the second example, they propose a new explanation for experimental results from a previous work.

I think this web would be very helpful for those working on this topic.

General comments:
This work seems to belong to a very specific field and to be directed to people with extended experience. It would hardly be used by someone out of that field. Taking that into account and Plos ONE being a very general journal, I think that the introduction is weak and does not properly present for neophytes the context, what the application does, the meaning of the outputs and how to interpret them.

Elements that apparently have important influence in the real behavior of the system, like the biolinker and the oxide layer, are almost not mentioned, they are just named in the introduction. How do they influence the system? How are they taken into account in the calculations? This should be described in the article.

Although the definition of an open source software does not mention free download availability, it is commonly agreed that distribution should be without restriction. "Can be obtained from the authors" is already a restriction and authors should reconsider the open-source label.

Specific comments:
In the web application, it would be helpful to place next to the input boxes a recommended maximum and minimum value for each option. Using a "<SELECT" html tag instead of an "<INPUT" tag for the "NW Type" field would make sure that only one of the two possible options will be selected.

Regarding the Jmol applet and the possibility to adjust the orientation of the biomolecule, it would be helpful to be able to save the new position so it could be used for other runs, ensuring reproducibility.

According to the web page, CTL + Left-mouse key is to translate the view. This key combination did not work for me, however CTL + Right did.  This should be corrected.

Page 5 line 56 -  p6 L7, authors assume that "all biomolecules are oriented in the same way", which makes sense if all are bound at the same residue and are influenced by the same charges, but authors do not provide an explanation or a reference to support this.

Page 8 line 15, authors use the word nanodevice like it was a perfect synonym of nanowire, is that correct?

In the same page line 31, Figure 1S is mentioned. Is it Figure 14 of the supporting information?

In page 9 line 47, I recommend to remove the word "completely" from the sentence "completely platform independent". The Jmol applet did not work properly in my Fedora 12 workstation (and Jmol does)

According to section S1.2 "all positions in the antibody sequence where mutated to Glycine". How the results of such an unrealistic molecule can be applied to a real experiment where amino acids of the antibody do have charges?

Figure 12 presents 2 graphics, to improve they comparison both should have the same maximum value for the ordinate axis.

[NOTE: If reviewer comments were submitted as an attachment file, they will be accessible only via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

Thursday, June 7, 2012

PhD fellowship in molecular drug research at the University of Copenhagen

The Faculty of Health and Medical Sciences, University of Copenhagen is pleased to announce that a PhD fellowship will be available from 1 September 2012 or as soon as possible thereafter. Applications are invited for the three-year fellowships from candidates that hold or expect to hold a master's degree in a field relevant to the following project:
The driving forces for recognition of drug compounds by cytochrome P450 enzymes - Computational chemistry studies on thermodynamics of binding. Supervisor: Associate Professor Lars Olsen, Department of Drug Design and Pharmacology (email:

An applicant with experience in computational chemistry (in particular molecular dynamics simulations), thermodynamic studies or protein-ligand studies will be preferred. Experimental experience with handling proteins will also be an advantage.

The project is part of the Faculty’ collaboration with the Leiden/Amsterdam Centre for Drug Research and are expected to lead to a double PhD degree at the University of Copenhagen and Vrije University Amsterdam (
see press release).
The PhD student will spend a significant part of the time in Amsterdam, and fulfil the academic requirements for both Universities. In Denmark, the PhD fellowship is to be completed in accordance with the 
Ministerial order on the PhD programme at the universities (PhD order) from the Ministry of Science, Technology and Innovation and the Regulations and guidelines for the conferment of the PhD degree by the Faculty .

The terms of employment are stated in the agreement between The Danish Confederation of Professional Associations and the Ministry of Finance. 
As an equal opportunity employer, the Faculty of Health and Medical Sciences invites applications from all interested candidates regardless of gender, age, ethnic origin or religion.
For further information, applicants may contact the main supervisor.
How to apply
STEP ONE: Make the following pdf-files:
  1. Letter stating the interest and qualifications for the project (max. one page)
  2. Full CV
  3. Master's degree diploma (including grade transcripts for bachelor’s and master’s degrees)
  4. Possible publication list
  5. Possible references
  6. Applicants with a Master's degree from abroad should also enclose a short description of the grading scale used. 
STEP TWO: Apply on-line by filling in the application form below and uploading the pdf-files.
STEP THREE: Print the pdf-files and send one hard copy in an envelope marked “PhD September 2012 LACDR" to:
University of Copenhagen
Faculty of Health and Medical Sciences
Personnel Office
Universitetsparken 2
DK - 2100 Copenhagen
The hard copy has to be received at the Faculty of Health and Medical Sciences, Personnel Office before the application deadline. Please do not send the application directly to the main supervisor, all applications should be sent to the Personnel Office.
Deadline for applications: Tuesday 17 July 2012 at 12 o'clock noon.  
Evaluation process: Applications will be handled and processed by the main supervisor and by the Scholarship Committee. An answer as to the granting of the fellowship can be expected appr. 4 weeks after application deadline. 

Saturday, June 2, 2012

Computational Chemistry Highlights: some numbers

Excerpt from an email I sent out to the CCH editors:

CCH has received 8401 page views to date (according to  CCH has 80 subscribers on Google Reader, 38 twitter followers, 24 Google+ followers, and 13 Facebook followers.  Not bad for a site that is roughly 3 months old.

The top 5 viewed posts of the last 30 days are (The page views reflect views where people have specifically clicked the link to the highlight):

Computational Design and Selection of Optimal Organic Photovoltaic Materials highlighted by Jan Jensen on May 20th  with 184 views

ROBIA and Dolabriferol highlighted by Dean Tantillo on May 6th  with 155 views

Steric Crowding Can Stabilize a Labile Molecule: Solving the Hexaphenyethane Riddle highlighted by Shason Shaik on April 16th  with 97 views

Energy Decomposition Analysis in Solution Based on the Fragment Molecular Orbital Method highlighted by Dmitri Fedorov on May 18th  with 93 views

Hydrogen-bond stabilization in oxyanion holes: grand jeté to three dimensions highlighted by Robert Paton on April 14th  with 90 views

Friday, June 1, 2012

Revised version of first PLoS ONE paper

The first paper has been revised after the reviews came back and is now sent back to PLoS ONE. We've given a detailed response to all points raised by the reviewers.

The supp. info. has also been submitted to as a separate submission, but as it needs to be published as well, I am still waiting for that to happen. This post will be updated to reflect it.

update June 5th, 2012: The updated pre-print is now available. However, it appears that you cannot have separate supplementary material submissions which makes sense if you ask me. There is, however no way to include this material other than append it to the raw tex-file which really puzzles me. Right now the supplementary material is thus not really available to anyone but the reviewers. sigh.

A few notes about the re-submission process. The first submission came back stating:

1.  Can you please upload an additional copy of your revised manuscript that does not contain any tracked changes or highlighting as your main article file.  This will be used in the production process if your manuscript is accepted.  Please amend the file type for the file showing your changes to Revised Manuscript w/tracked changes. Please follow this link for more information:

2.  Please ensure that you refer to Figure 5 in your text as, if accepted, production will need this reference to link the reader to the figure.

3.  Please ensure that you refer to Supplementary Table S3 in your text as, if accepted, production will need this reference to link the reader to the table.

Its actually nice that points 2 and 3 were found as it was some mishap in the latex-referencing that went unnoticed. Silly thing when your equation numbers and your figure numbers align.

Regarding the first point, it was not entirely obvious that they wanted both the tagged (which I submitted) and the un-tagged - moreover, they request the PDF file "for publishing" which is even more weird. Alas, I ended up submitting both and are now hoping this will satisfy the PLoS ONE staff.