Sunday, August 25, 2013

Monday, August 19, 2013

Seminar: Open Source Drug and Catalyst Discovery

Open Source Drug and Catalyst Discovery
Dr +Matthew Todd  School of Chemistry, The University of Sydney; @mattoddchem

September 12, 2013 at 10:15 in Aud 5 HCØ, University of Copenhagen

Science today is typically practiced by groups working in isolation, frequently with barriers to the sharing of data that arise from our need to protect intellectual property. Papers frequently do not disclose negative results, and the danger of being “scooped” often arises because we are unaware of what others are doing.

The open source software community works in a very different way, sharing data and ideas freely as part of highly distributed meritocratic projects where anyone can participate. In the last few years we have successfully applied these principles to the practice of experimental organic chemistry.1 We showed that the discovery of a method for the preparation of an important, enantiopure drug was accelerated by the project being completely open.2 We have since started the world’s first open source drug discovery project for the treatment of malaria that has already identified highly promising picomolar leads in whole-cell assays.3 Beyond drug synthesis and discovery, our laboratory has started several projects in basic organic synthetic methodology and catalyst discovery, acting as seeds for the contributions of diverse chemists from academia and industry.4

1 Open Science is a Research Accelerator, M. Woelfle, P. Olliaro and M. H. Todd, Nature Chemistry 2011, 3, 745-748.
2 Resolution of Praziquantel, M. Woelfle, J.-P. Seerden, J. de Gooijer, K. Pouwer, P. Olliaro and M. H. Todd, PLoS Negl. Trop. Dis. 2011, 5(9): e1260.
4 For example 

Thursday, August 15, 2013

Review of Protein structure validation and refinement using amide proton chemical shifts derived from quantum mechanics

The reviews for +Anders Steen Christensen's paper, submitted to PLoS ONE on 2013.07.24, are in.

There are 3 main points raised by the reviwer:

1. Do ProCS-predicted chemical shifts predicted using all high resolution structures of ubiquitin compare poorly with experiment?

That's not too tough to find out.

2. "Can the authors show improved structure validation characteristics when using more conventional evaluation criteria (e.g using the Protein Structure Validation Software (PSVS), or RDC Q factors)?"

The problem is were dealing with ensembles of 1000s of structures, so unless we can find an downloadable version of PSVS, this won't be possible.  Also, I don't believe PSVS scores report on anything directly associated with backbone amide hydrogen bonds, so I am not sure what the answer would tell us.

Wrt RDC Q factors, that'll take a while to write the code for questionable benefit.  Should we argue on this or try to do it?

3. Depositing the structures.  We need to find a place that'll accept 10-20 GB files.

From: PLOS ONE <>
Date: Wed, Aug 14, 2013 at 6:49 AM
Subject: PLOS ONE Decision: Revise [PONE-D-13-30410]
To: "Anders S. Christensen" <xxx>

Protein structure validation and refinement using amide proton chemical shifts derived from quantum mechanics

Dear Mr. S. Christensen,

Thank you for submitting your manuscript for review to PLOS ONE. After careful consideration, we feel that your manuscript will likely be suitable for publication if it is revised to address the points below. Therefore, my decision is "Minor Revision."

We invite you to submit a revised version of the manuscript that addresses the three points that reviewer #1 raises. The first point in particular concerning errors in chemical shifts due lack of ensemble sampling in x-ray structures may require considerable work but would be of serious benefit to thrills.

We encourage you to submit your revision within forty-five 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. Before uploading, you should proofread your manuscript very closely for mistakes and grammatical errors. Should your manuscript be accepted for publication, you may not have another chance to make corrections as we do not offer pre-publication proofs.

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,

Academic Editor

[Note: HTML markup is below. Please do not edit.]

Journal requirements:

When submitting your revision, we need you to address these additional requirements.

1) Please ensure that you refer to Supplementary Figures S1, S4 and S5 in your text as, if accepted, production will need this reference to link the reader to the Figures.

2) Thank you for stating the following in the Financial Disclosure section:

ASC is funded by the Novo Nordisk STAR PhD program. MB is funded by the Danish Council for Independent Research (FTP, 09-066546). WB and K L-L are supported by a Hallas-Møller stipend (to K L-L) from the Novo Nordisk Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

We note that you received funding from a commercial source Novo Nordisk.

Please respond in the cover letter to declare this commercial funder, along with any other relevant declarations relating to employment, consultancy, patents, products in development or marketed products etc) and if true, you should also confirm that this does not alter your adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in our guide for authors by including the following statement: "This does not alter our adherence to all the PLOS ONE policies on sharing data and materials." Please note that we cannot proceed with consideration of your article until this information has been declared.

We can make any changes on your behalf.

Please be assured that it is the standard PLOS ONE policy to ask authors to declare any potential competing interests, for the purposes of transparency. This declaration does not affect the review process. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests:

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Please explain (optional).

Reviewer #1: The manuscript builds on earlier work for 1H chemical shift calculation using QM methods to parameterize a novel method (ProCS) to rapidly predict 1H chemical shifts by adding the various terms, assuming their additivity applies, which the authors demonstrate to be a good approximation within the errors that one has to deal with. The 1H chemical shift prediction errors with ProCS remain high compared to the empirical programs "on the market" today, but as the authors argue (probably correctly) these prediction errors are dominated by structural noise, and empirical methods have been optimized to be as insensitive as possible to errors in the input coordinates.

They then take advantage of this extreme sensitivity to structural errors by including the difference between ProCS and experimental shift as a "constraint" when refining the structure with their MCMC method, and validate the improvement in structural quality by showing improved agreement between experimental h3JNC' couplings and values predicted on the basis of H-bond geometry by the Barfield equation, showing dramatic improvements in agreement (i.e., presumably in H-bond geometry).

Although the method appears computationally more expensive than the popular CAMSHIFT program, it clearly offers a new and potentially more powerful approach for refining structures directly against amide 1H shifts.

I believe the work is potentially important and of suitable quality for publication in PLOS One, but would like to see the two minor issues raised below addressed prior to its publication (as I presume many readers will have the same questions).

1. The authors comment that the inability to reproduce the experimental chemical shifts by QM methods may be caused by the fact that X-ray structures represent merely one snapshot of what in real life is a statistical ensemble (p.4). If that is true, one would expect all high resolution structures of ubiquitin to agree rather poorly (there are at least a dozen with X-ray resolution <=1.8 A). Is this true? Is it also true that ensembles refined against the experimental h3JNC' couplings (e.g. 2K39 or 2KOX) fit better than single structures (e.g. 1D3Z)?

2. Both HN chemical shift and h3JNC' are dominated by H-bond length, and the improved fitting of chemical shifts after refinement is therefore perhaps a bit circular. Can the authors show improved structure validation characteristics when using more conventional evaluation criteria (e.g using the Protein Structure Validation Software (PSVS), or RDC Q factors)?

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Please explain (optional).

Reviewer #1: (No Response)

3. Does the manuscript adhere to standards in this field for data availability?

Authors must follow field-specific standards for data deposition in publicly available resources and should include accession numbers in the manuscript when relevant. The manuscript should explain what steps have been taken to make data available, particularly in cases where the data cannot be publicly deposited.

Reviewer #1: No

Please explain (optional).

Reviewer #1: The atomic coordinates of the refined structures of the three proteins studied should be deposited.

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors below.

Reviewer #1: Yes

Please explain (optional).

Reviewer #1: (No Response)

5. Additional Comments to the Author (optional)

Please offer any additional comments here, including concerns about dual publication or research or publication ethics.

Reviewer #1: (No Response)

6. If you would like your identity to be revealed to the authors, please include your name here (optional).

Your name and review will not be published with the manuscript.

Reviewer #1: (No Response)

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible 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, August 7, 2013

The end of a saga: "In silico screening of 393 mutants facilitates enzyme engineering of amidase activity in CalB" accepted in PeerJ

The reviews for Martin's last paper (which we submitted 28 days ago) came back July 31st and can be found below.  Before I could even present them in a blogpost Martin had a response ready, which was sent in late yesterday and promptly accepted (I am glad I managed to upgrade before that happened!).

When I say the end of a saga here is what I mean:

The paper is submitted to arXiv Sept 20, 2012 (almost a year ago)
The papers is rejected without review by JCIM and PCCP
Journal of Molecular Catalysis B: get your act together
Original PLoS ONE reviews
Our rebuttal
The rejection
Our appeal

Anyway, I am really happy the paper found a home at +PeerJ, especially considering the only remaining alternative.

Thank you for your submission to PeerJ. I am writing to inform you that in my opinion as the Academic Editor for your article, your manuscript "In silico screening of 393 mutants facilitates enzyme engineering of amidase activity in CalB" (#2013:07:643:0:0:REVIEW) requires some minor revisions before we could accept it for publication.

The comments supplied by the reviewers on this revision are pasted below. My comments are as follows:

Editor's comments

Please address critical points raised by the first reviewer.

If you are willing to undertake these changes, please submit your revised manuscript (with any rebuttal information*) to the journal within 45 days.

* A rebuttal letter and any tracked changes can be added to the file uploads page under the "Revision response files" section. Please also upload a clean untracked version for production purposes to the primary files section and replace your previous manuscript. Accepted formats for the rebuttal letter and tracked changes are: docx (preferred), doc, and PDF.

Academic Editor for PeerJ

Reviewer Comments

Reviewer 1

Basic reporting

No Comments

Experimental design

No Comments

Validity of the findings

No Comments

Comments for the author

This manuscript describes in silico screening of CalB mutants for enzymatic amidase activity. Then the computational results are benchmarked against experimental studies. The computational approach gives reasonable results in general -- the authors demonstrate that 15 out of 22 mutants are correctly predicted in qualitative activity. The manuscript is scholarly and well written. The methods are complete and clear. The data are new and appear to be true. I recommend publishing with minor revision.
I have a few minor suggestions/questions.
1. In table 1, two columns are both labeled with “Cat.” The authors need to make more detailed labels to distinguish (one from Exp. and the other is from Calc.). Also, the authors need to include the cutoff of 12.5 kcal/mol in the table legends otherwise it is difficult for readers to correlate calculated barriers with calculated cat.
2. In pg. 8, the authors state that the cutoff is done purely for a post hoc comparison of experimental and computed data. And they used 12.5 kcal/mol as cutoff. The authors need to expand this section to give detailed descriptions about how they reach the value of 12.5 in their study.
3. For results and discussion part, the two subtitles are “Set S” and “Set L”. It might be useful to guide readers if the authors can use more detailed subtitles which can generally summarize their results.
4. In the last part of results and discussion, the authors state that I189G as a single mutant is counterproductive but lowers the barrier of G39A-A141Q-L278A. This would suggest there are couplings between I189 and G39/A141/L278. While it is difficult to figure out such kind of couplings, one simple question is, is I189 close to G39/A141/L278 in the structure.

Reviewer 2

Basic reporting

Meets all necessary criteria

Experimental design


Validity of the findings


Comments for the author

This is an excellent paper, nicely demonstrating the utility of a practical computational modelling approach to the prediction of enzyme activity. The method uses semiempirical quantum chemical methods to model amidase reactivity in a lipase. This is thorough work of high quality. The paper is well written and the results are analysed and presented in appropriate detail. The results will be of wide interest. This is a demonstration of a method that will find real industrial application, as well as in other contexts. The paper is suitable for publication essentially as is. A minor point is that some of the references might be lacking information (e.g. refs 27 and 28 do not look complete as written). Also, the authors might want to comment a little more on how amidase activity is achieved. There is wide debate about amidase versus esterase activity, and, while this is not the focus here, comparison with enzymes such as fatty acid amide hydrolase, which has been the subject of much modelling work, could be useful (e.g. a little more discussion on what specific features may provide amidase activity and how the designed amidases compare to natural amidaases). This could assist in future rational design (as well as in testing the quantum chemical methods by comparisons on related reactions.

Friday, August 2, 2013

Open access licenses: It's all about reuse - part 2

This post is a response to this post by Rosie Redfield.
"It's time for open-access advocates and especially publishers to take on the responsibility of informing authors of all the consequences, not just the good ones."
I think this is the fundamental disconnect in the discussion.  I think most OA advocates on-balance don't see the commercial use of OA content allowed by the CC-BY as a bad thing.  I don't think the "The authors shouldn't see this as harmful" responses you mention in your comments are blaming the authors.  Rather, people are trying to tell them something important about the fundamental motivation behind OA: gratis vs libre (  Are you just free to read the paper or can you do something with it?

If you really think about it any license but CC-BY (or CC0) place severe (and often unexpected) limitations on use.

Some examples: publishing under CC-BY-NC means that figures cannot be used in textbooks, course packs for sale at the bookstore, blogposts on http://rrresearch.fieldofscience.COM/, lecture notes for students paying for the signature track in this MOOC:, any company that charges anything at all to cover the cost of distributing papers on DVDs to regions with poor internet connections, and, most important, hundreds of other good uses no-one has thought of yet.
Publishing under CC-BY-SA means that if you use a single figure from such a paper in your lecture notes, then you must license your notes under CC-BY-SA.  The same goes for using a CC-BY-SA image on a blogpost.  One could make a good argument for the fact now you have to license your entire blog under that license.  This is why CC-BY-SA is called a viral license: a single instance of use "infects" the site/file/book/course and "spreads" the license.  For people who don't want to license their work under the CC-BY-SA license, work published under the CC-BY-SA license is hard to use.

CC-BY (or CC0) removes these problems, so your reasons for using anything else have better be well thought-through.*  I would be very interested in some detailed reasons for why having your OA article included in a compendium by a commercial publisher is a bad thing and why stopping that from happening outweighs other problems associated with licenses other than CC-BY or signing your copyright away.

*That includes signing your copyright over to commercial publishers (i.e. when authors "rethink their use of open-access").  Try to ask permission to use a figure from such a publication for much of anything and you'll find that these figures are very much for sale by commercial publishers, without asking authors (why? they don't have copyright) and for a lot more than $80.

Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 Unported License.   

Thursday, August 1, 2013

Martin's latest paper is 'Featured Article' on PeerJ

Martin's paper has been recently accepted in PeerJ, and it is now showcased as 'Featured Article' on the journal web page. Way to go!
The article is available here.