Saturday, May 26, 2012

Two versions of the Debye-Hückel limiting law

The Debye-Hückel limiting law is usually written for the mean activity coefficient$$\log(\gamma_\pm)=-|z_+z_-|A\sqrt{I}$$ However, occasionally you will also see it written for the (unmeasurable) activity coefficient of each individual ion $$\log(\gamma_+)=-z_+^2A\sqrt{I}$$ For the compound $M_pX_q$ $$\gamma_\pm=(\gamma_+^p\gamma_-^q)^{1/(p+q)}$$ But that implies $$\log(\gamma_\pm)=-\frac{(pz_+^2+qz_-^2)}{p+q}A\sqrt{I}$$I couldn't find the connection between these seemingly different definitions of $\gamma_\pm$ anywhere on the web so here it comes.  It's actually rather simple in hindsight.  Charge neutrality dictates $$pz_++qz_-=0$$ and this means $$pz_+^2+qz_-z_+=0\\ pz_+z_-+qz_-^2=0\\pz_+^2+(p+q)z_-z_++qz_-^2=0 $$which is what we need.  For some reason $z_-z_+$ is usually written $-|z_-z_+|$.

One things that's usually not mentioned is that the activities based on the mean and ionic activity coefficients will be different, i.e. $\gamma_\pm b_+ \ne \gamma_+ b_+$.  But of course things like the equilibrium constant will of course.

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Friday, May 25, 2012

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

Casper very recently submitted this paper to PLoS ONE and deposited it at

The use of fragmentation methods to treat very large systems is currently somewhat troublesome due to the complexity of the input files these programs require. We've made a tool called FragIt to generate run-ready input files which lowers the barrier of entry into this fragmented world.

Near linear scaling fragment based quantum chemical calculations are becoming increasingly popular for treating large systems with high accuracy and is an active field of research. However, it remains difficult to set up these calculations without expert knowledge. To facilitate the use of such methods, software tools need to be available for support, setup and lower the barrier of entry for usage by non-experts. We present a fragmentation methodology and accompanying tools called FragIt to help setup these calculations. It uses the SMARTS language to find chemically appropriate substructures in structures and is used to prepare input files for the fragment molecular orbital method in the GAMESS program package. We present patterns of fragmentation for proteins and polysaccharides, specifically D-galactopyranose for use in cyclodextrins.

The source code is available at github. You can also try out a web-version at

Tuesday, May 22, 2012

PLoS ONE resubmission trouble

2012.05.28 Update: Point 2 was also their mistake.  Another sincere apology.

2012.05.25 Update: The manuscript was sent back again because of point 2.  I don't understand it.  Table 1 and 2 is referred to on page 5 and 6 respectively.  Very annoying.

2012.05.24 Update: Point 1 was a mistake.  I even received their sincere apologies. We should be able to ship it off later today.

Just go the email reproduced below.  I am really puzzled about point 1 as we formulated an extensive response and have sent an email to the editor asking for clarification.

Meanwhile we'll check point 2, which is a little annoying since the paper hasn't been accepted yet.

A Computational Methodology to Screen Activities of Enzyme Variants

Dear Dr. Jensen,

Thank you for submitting your manuscript entitled "A Computational Methodology to Screen Activities of Enzyme Variants" to PLoS ONE.  Your manuscript files have been checked in house but before we can proceed, we need you to address the following issues:

1)  Please amend your Response to Reviewers letter to include a point by point response to each of the points made by the Editor and / or Reviewers.

2)  Please ensure that you refer to Table 1 and 2 in your text as, if accepted, production will need this reference to link the reader to the Table.

Your manuscript has been returned to your account. Please log on to PLoS Editorial Manager at to access your manuscript.

Your manuscript can be found in the "Submissions Sent Back to Author" link under the New Submissions menu. After you have made the changes requested above, please be sure to view and approve the revised PDF after rebuilding the PDF to complete the resubmission process.

Please note that these changes have been requested to comply with submission guidelines and your manuscript will *not* be sent to review until you have fully adhered to our requests.  Once your paper has been seen by an Editor we may return it to you for further information or amendments.

Thank you for submitting your work to PLoS ONE.

Kind regards,

Shailja Singh

Monday, May 21, 2012

Revised version of second PLoS ONE paper

Based on the reviews we have submitted a revised version of the second paper we sent to PLoS ONE.  The cover letter detailing our response can be found here.

Fingers crossed.

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: [] on behalf of PLoS ONE []
Sent: Thursday, April 26, 2012 4:16 PM
To: Casper Steinmann Svendsen
Subject: PLoS ONE Decision: Revise [PONE-D-12-06195]

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

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 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: 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.

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.

[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, May 10, 2012

Postdoctoral position in QM/MM at Kings College

Kings College, London

Reference Number:    R6/JRC/317/12-MC
Application Deadline:    21/05/2012

A two year Research Associate post in theoretical and computational chemistry is available in the Chemistry Department, School of Biomedical Sciences, King's College London. The successful applicant will join Edina Rosta's group using QM/MM simulations to study the reaction mechanism of phosphate hydrolysis and transfer in enzymes. The specific project is focused on QM/MM modelling of kinase activities and kinetic modelling of signalling pathways. The project will estimate kinase activities from QM/MM simulations, aiming to integrate these data into large scale kinetic network models of signalling pathways.

Candidates must be highly motivated scientists, with a Ph.D. in theoretical and computational chemistry or biological physics. Candidates with a physics background are particularly encouraged to apply. Ideal candidates would have prior experience with Linux/Unix and computational data analysis, and would have worked in at least one of the areas of (i) molecular dynamics, (ii) quantum chemistry, (iii) structural biology/homology modelling, or (iv) modelling of kinetic networks.

Salary: Grade 6, £31,020 to £37,012 plus £2,323 London Allowance per annum, depending on qualifications. Duration of appointment: fixed term for 2 years. Starting date is 1st Sept 2012 or as soon as possible thereafter.

For inquiries, please email Dr. Edina Rosta at Edina.Rosta at .

Friday, May 4, 2012

BioFET-SIM Web Interface: Implementation and Two Applications

Martin submitted a new paper to PLoS ONE:

BioFET-SIM Web Interface: Implementation and Two Applications Martin R. Hediger, Jan H. Jensen, Luca De Vico. arXiv

The paper was submitted April 27 and deposited on arXiv the same day.

We present a web interface for the BioFET-SIM program. The web interface allows to conveniently setup calculations based on the BioFET-SIM multiple charges model. As an illustration, two case studies are presented. In the first case, a generic peptide with opposite charges on both ends is inverted in orien- tation on a semiconducting nanowire surface leading to a corresponding change in sign of the computed sensitivity of the device. In the second case, the binding of an antibody/antigen complex on the nanowire surface is studied in terms of orientation and analyte/nanowire surface distance. We demonstrate how the BioFET-SIM web interface can aid in the understanding of experimental data and postulate alternative ways of antibody/antigen orientation on the nanowire surface.

Martin made a really nice screencast of the interface. 

My presentation at the IRENE conference

Thursday, May 3, 2012

Computing molecular properties with molecular dynamics - part 2

These videos represent a lecture from my course Molecular Statistics that gives brief introduction to computing molecular properties with molecular dynamics.  The lectures are in Danish.  The lecture notes can be found here.  See also this blog post.

a. Computing molecular properties
b. Computing the free energy difference part 1
c. Computing the free energy difference part 2

Technical details
The first video was made with ScreenFlow and Molecular Workbench
The remaining videos was made with an iPad, Apple head-phones, the Explain Everything app, and a Bamboo Stylus.

Tuesday, May 1, 2012

A brief introduction to periodic boundary conditions (in Danish)

These videos represent a lecture from my course Molecular Statistics that gives brief introduction to periodic boundary conditions.  The lectures are in Danish.  The lecture notes can be found here.  See also this blog post.

a. The boundary problem
b. Periodic boundary conditions: a sketch
c. Periodic boundary conditions: an animation
d. Cutoffs - Part 1
e. Cutoffs - Part 2

Technical details
The first video was made with ScreenFlow and Molecular Workbench
The remaining videos was made with an iPad, Apple head-phones, the Explain Everything app, and a Bamboo Stylus.

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