Conformer search with RDKit

I'm teaching myself how to use RDKit.  Here is code for conformer search using RDKit that also computes the energy of each conformer using the MMFF94 force field.

Comments welcome


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Thoughts from the Gordon Research Conference on Computational Chemistry

Here are some of the things I took away from attenting the GRC on Computational Chemistry

Tweeting
The GRC had very strict "off-the-record" rules to encourage the presentation of unpublished results. However, most speakers devoted at least half their talks to published results and I and others - especially Marc van der Kamp - Tweetet some of these papers under the hashtag #compchemGRC.

Furthermore, I also explicitly waived my "off-the-record" rights at the beginning of my talk and encouraged Tweeting.  I also shared my slides on Twitter - before the conference and immediately before my talk.  Seeing these slides on Twitter, FX Coudert alerted me to the fact that PM6 is now fully implemented in CP2K, which is could be very useful for our work.

Open Access
I talked to a few people about my OA philosophy.  Here is what I put on my CV

"My publication policy since 2012:  If a paper has a shot at high impact journals such as JACS or PNAS then I will submit there. However, the majority of my papers are method development papers, which will be submitted to open access journals such as PLoS ONE or PeerJ as I fail to see a difference in impact between these journals and journals such as Journal of Chemical Theory and Computation and Journal of Computational Chemistry where I used to publish before."

However, it really doesn't have to be an all or nothing decision.  My best advice is one paper at a time.  Just try it once and see what happens.

For me "impact neutrality" has become just as important as OA.  It is so very liberating to just write down what I did and what I found rather than trying to put everything in the best possible light with elaborately constructed "technically-correct-but-not-really-telling-the-whole-story" paragraphs.

Reproduceability
Speakers usually show their "best" work at conferences and precious speaker time is generally not wasted on pitfalls and caveats. It is easy to get the impression that everything is going great for everyone else, while you are struggling with your own projects. Furthermore, when you see something potentially wonderful that you want to try but you just know from experience that it won't be so easy as the speaker makes it sound and, in fact, will be hard to reproduce from the published papers alone. (This is no reflection on any one particular speaker at the conference).

This general sentiment was shared by a number of people I talked to.  It's not a new problem but I do believe it is a  growing one in part because research projects are getting more complex making it nearly impossible to describe all steps in sufficient detail to make it reproduceable. The only solution is, in my opinion, to make everthing available as supplementary material. Tar the whole thing - input files, output files, submission and analysis scripts, spreadsheets, etc - and put it on a server such as Figshare.

Funding
The usual conference conversation starts with "Hey X, how are things going?", "Oh, fine, and you?", "Oh, fine."  But one person responded "Writing a lot of proposals and getting them rejected."  I really appreciated this honesty, and it makes me feel less bad about my own rejections. A few weeks ago I had a similar talk with another colleagues about the possibility of having no PhD students in the not-too-distant future and how this affects the choice of research projects one can take on.  I think a lot of scientists are going through the same type of thing and it is important to be open about it.

Co-vice chair election (This will only make sense to people who were at the meeting, and that's fine)
A few people asked me why I effectively withdrew from consideration just before the vote. The short answer is that it didn't know for sure who else was running, nor that the candidates would be split up in two group, until that morning. Had I thought a little faster, I probably could have gotten my name removed just in time. But I am not a fast thinker at the best of times and certainly not at 8:30 am.


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Finding disordered residues in an NMR ensemble

Note to self: here's how you identified disordered residues in the NMR ensemble 2KCU.pdb

1. In Pymol: "fetch 2kcu"

2. Action > align > states (*/CA)
2016.08.07 update: the above command also aligns the tails.  Use "intra_fit (2kzn///6-158/CA)"

3. "save 2kcu_aligned.pdb, state=0"

4. In terminal: grep CA 2kcu_aligned.pdb > lis

5. python disorder.py

disorder.py (given below) calculates the standard deviation of the x, y, and z coordinate of each CA atom ($\sigma_{x,i}, \sigma_{y,i}, \sigma_{z,i})$. It then averages these three standard deviations for each CA atom $(\sigma_i)$.  To find outliers, it averages these values for the entire protein $(\langle \sigma_i \rangle)$ and computes the standard deviation of this average $(\sigma_{\langle \sigma_i \rangle})$. Any residues for which $\sigma_i > \langle \sigma_i \rangle + \sigma_{\langle \sigma_i \rangle}$ is identified as disordered.

Here I've colored the disordered residues red (haven't updated the picture based on Step 2-change yet)

Yes, I know: "the 1970's called and want their Fortran code back". How very droll.



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Reproducing stats or verbose output from LINEST command in Excel or Google Sheet in Python

The python code above reproduces the output produced by the LINEST(y;x;true;true) command in Excel [LINEST(y,x,true,true) in Google Sheets] with a csv file as input.  In the csv file I have assumed that the x and y columns are labelled "x" and "y" respectively.  This page has a good explanation of the output (pdf).



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2nd Reviews for Prediction of pKa values using the PM6 semiempirical method

2016.07.15: Update: our rebuttal can be fund here.  Manuscript resubmitted.

The 2nd round of reviews on our latest PeerJ submission came in on July 7th.  The first round of round of reviews and a link to our response can be found here.

Editor's Comments

MINOR REVISIONS

Thank you for your efforts at addressing the reviewer's comments. In spite of that, the reviewers (and myself) still think that additional data should be moved from the Supporting Information to the main text as tables/graphs. Specifically:

-per reviewer 1's request, please include the ref. pKa data in table 1. The Supporting Material deposited in figshare is very complete, but it will enormously help the reader (and make your paper much more persusive at first reading) if the most salient pieces were included in the paper itself. 

- contra reviewer 1's comment, I do acknowledge that p.799 of the quoted Stewart (2008) reference describes the pKa computation procedure which generated the data present in http://openmopac.net/pKa_table.html. This method (also used by Rayne) as well as the method by Juranic, however, do not computes pKa from the energy difference itself, but from an empirical fit of the O-H bond distances and approximate charges (or N and H charges, plus a dummy variable stating whether the amine is primary, secondary or terciary, for Juranic, 2014). These pKa computation approaches are therefore fundamentally different from the one used in your paper. Your references to this literature in the introduction, however, do not make this clear enough. Please improve this to clearly compare the competing methods for PM6-based pka computations to the your approach.

-Do include the statistical data regarding slope, R-squared and outliers. A motivated reader may easily graph the data you have computed (and which are present in the spreadsheet referred to in your figshare area), but your explanation and discussion would be much more readable, and certainly more persuasive, if you included those graphs, slopes and correlation coefficientes in the paper. That analysis shows more clearly than the aggregat tables exactly where PM6 affords better correlation/slope that even CBS-4B3 (pyridines), the identity of the outliers, how poorly all methods (even CBS-4B3) correlate to experimental pKa in amines (in spite of a seemingly low 0.2 MAD for CBS-4B3), etc.

-per reviewer 2's request (and also related to my previous request which I may not have worded clearly) please add data regarding the likely origin of the errors in the outliers: do they come from gas phase energies or the solvation? A simple comparison of the B3LYP gas-phase energy changes (on PM6-optimized geometries, to reduce computational effort) and solvation effects might be enough to tell whether the gas-phase acidities (and/or solvation) of PM6 generally track the DFT results.

Reviewer 1 (Anonymous)

Comments for the Author

Reviewer Comments – Reviewer 1

The authors have not adequately responded to any of the concerns raised in my original review. My original comments are shown first. The authors’ responses are shown next; and my further responses to them are shown below.

(1) Basic reporting 

This is an interesting manuscript, but a frustrating aspect is that the experimental pKa values used for comparison are not included for most compounds. These could easily be added to Table 1. In fact, the best solution would be to modify Table 2 to give the calculated pKa values from the various methods along with the experimental values.

Authors: The values are already provided in Supplementary Materials

The copy I received contained no reference at all to “Supplementary Materials”. If these materials are available directions for accessing them should be clearly presented in the normal position just before the References.

(2) Also, the authors should refer somewhere to the very relevant PM6 pKa calculations by Jimmy Stewart given in http://openmopac.net/pKa_table.html. 

Authors: We already refer to this approach in the introduction (Stewart 2008).

The reference Stewart (2008) concerns proteins and has nothing at all to do with pKa estimates. As clearly indicated, the relevant Stewart study is not a formal publication, but has been made widely available to workers by Stewart on the web page as indicated. Apparently the authors didn’t even bother to look at it.

(3) Validity of the findings 

It would be very helpful if the authors would provide a figure comparing the calculated and experimental values, and include in the text the relevant equation with proper statistics (n, r2, s, F) along with the uncertainties for the slope & intercept. (See, e.g., the book by Shields & Seybold on this topic, or their WIRES article.) 

Authors: The statistical analysis the reviewer refers to is done in the context of a QSAR prediction of pKa from QM data, i.e. to gauge the accuracy a linear fit to be used in the prediction of unknown pKa values. The statistics used in this paper is just aimed at gauging the accuracy of the predicted values and, in our opinion, is more than adequate for the task. If the reviewer can explain how the requested statistics is to be used in the context of the current paper we will be happy to reconsider the request.

This is a standard way to compare not just QSAR results, but any studies in this field. It would be helpful, and I don’t understand the authors’ reluctance to include it.

Annotated manuscript

The reviewer has also provided an annotated manuscript as part of their review:

Reviewer 2 (Anonymous)

Comments for the Author

I thank the authors for the revised manuscript. I would still like the authors to address my second point as to what is the major source of error in these calculations, especially for the outliers. Is it the gas phase energies, or the solvation component?

Planned papers for 2016 - six months in

Pedro's post reminded me that mine was due

In January I wrote about the papers I plan to publish and made this list:

Submitted
None

Probable
1. Benchmarking of PM6 and DFTB3 for barrier heights computed using enzyme active site models.
2. pKa prediction using PM6 - part 1
3. Protein structure refinement using ProCS15 - starting from x-ray structure

Maybe
4. PM6 for all elements in GAMESS, including PCM interface
5. Protein structure refinement using ProCS15 - starting from 5 Å Cα RMSD
6. Vibrational effects on N amide chemical shifts
7. pKa prediction using PM6 - amines
8. Predicting binding free energies for CB7
9. Linear scaling HF-3c calculations by interface to FMO2 in GAMESS
10. Side chain chemical shift prediction with ProCS15
11. Rienstra-like chemical shift assignment in PHAISTOS

The status is

Published 

1. Benchmarking of PM6 and DFTB3 for barrier heights computed using enzyme active site models.

Submitted

2. pKa prediction using PM6 - part 1

Received "minor revision" verdict.  Sent back in last week.

Probable

3. Protein structure refinement using ProCS15 - starting from x-ray structure

Actively working on it. First draft about 2/3 done. It's a huge amount of work because I'm still new to the field and learning as I am writing. However, I am fairly confident that I'll get it published in 2016.

7. pKa prediction using PM6 - amines

The main issue here is whether we can automate all steps of the pKa calculation and based on what we have learned so far I am pretty sure we can. The main issue is the protonation. Once paper 3 is done I will start working on this.  The CPU requirements are not an issue so I am fairly confident that I'll get it published in 2016.

Maybe in 2016

*. Improved prediction of chemical shifts using machine learning

This wasn't even on the drawing board in January.  Lars spent a few months in Anatole von Lilienfelds lab working on increasing the accuracy of the ProCS15 data set  using machine learning. Calculations are still ongoing so I am a little hesitant to list it under "probable".

A companion paper in Scientific Data has also been discussed, 

Probably not in 2016

4. PM6 for all elements in GAMESS, including PCM interface

Jimmy is working on the first part.  The interface is there but debugging is really tough.  I think we will get it working in 2016 but getting a paper published this year is unlikely.

5. Protein structure refinement using ProCS15 - starting from 5 Å Cα RMSD

I think we will get most of the calculations done in 2016.

6. Vibrational effects on N amide chemical shifts

I had a visiting student working this. Bottom line: still no bug-free, black-box approach for computing vibrational that just works.  Much harder problem than I had anticipated.

8. Predicting binding free energies for CB7

Have some data but a long way to go yet.

9. Linear scaling HF-3c calculations by interface to FMO2 in GAMESS

This is actually working and being incorporated into the official version of GAMESS.  Not sure when we'll get around to generating data for a paper.

10. Side chain chemical shift prediction with ProCS15

Susanne is working on this but I doubt we will publish a paper on it in 2016. 

11. Rienstra-like chemical shift assignment in PHAISTOS

Still just an idea so far.

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Reviews for Prediction of pKa values using the PM6 semiempirical method

2016.06.21 Update: Here's our response

Reviews of our latest PeerJ submission is in after only 15 days.  This must be some kind of record!

Personal comments from the editor:

Table 4 shows dramatic differences between PM6-D3H+ and PM6 although the previous tables did not show very large differences between both semiempirical methods. Please discuss this.

How do the errors in PM6 or PM6-D3H+ gas-phase protonation energies (vs. experiment or high level computation) change when moving from primary to secondary and tertiary amines? I believe that the addition of a table with these data (with each tested amine treated separately) would be very helpful for the readers and future practitioners.

Reviewer 1 (Anonymous)

Basic reporting
This is an interesting manuscript, but a frustrating aspect is that the experimental pKa values used for comparison are not included for most compounds. These could easily be added to Table 1. In fact, the best solution would be to modify Table 2 to give the calculated pKa values from the various methods along with the experimental values. Also, the authors should refer somewhere to the very relevant PM6 pKa calculations by Jimmy Stewart given in http://openmopac.net/pKa_table.html.

Experimental design

In general this work is properly designed.

Validity of the findings

It would be very helpful if the authors would provide a figure comparing the calculated and experimental values, and include in the text the relevant equation with proper statistics (n, r2, s, F) along with the uncertainties for the slope & intercept. (See, e.g., the book by Shields & Seybold on this topic, or their WIRES article.)

Comments for the Author

After improvements, this manuscript will be of interest to many people attempting to calculate pKas, especially those dealing with high throughput applications.


Reviewer 2 (Anonymous)

Basic reporting

The paper is well-written and organised in a manner that was easy to read. I did find the background / literature research on the short side. Specifically, the isodesmic or proton exchange scheme was developed quite some time ago by various groups . See for example: (a) http://dx.doi.org/10.1063/1.1337862 (b) 10.1021/ct800335v and (c) 10.1021/jp107890p. These studies have laid out quite clearly the effectiveness of an isodesmic scheme for error cancellation, as well as its limitations (e.g. the need for a structurally similar reference with accurately known pKas). Another minor point is there should be a footnote to explain what "**" in Table 2 means.

Experimental design

The research question is well-defined, namely whether contemporary semi-empirical methods can provide cost-effective predictions of pKas. I do have a number of suggestions for improvement:

(1) Computational methods: It was not clear how the solvation free energies were computed - e.g. were these done on gas phase or solution phase optimised geometries? Strictly speaking, the gas and solution phase components of the solvation free energy should be computed on geometries optimised in the respective phases. How sensitive are the results to this choice?

(2) There is a lot of data condensed into the Tables which could actually be used to provide even deeper insights. For example, I would love to see a breakdown of the solution phase energies into the gas phase and solvation contributions as laid out in eqn (6). This would be useful for identifying the sources of errors especially for the outliers.

(3) The dataset molecules in Table 1 are structurally very similar (the substituents are mostly aliphatic groups). It would be interesting to see a more diverse selection of molecules (e.g. EWG and EDG) as the authors alluded to in their conclusion.

Validity of the findings

I think the conclusions are fair based on the results presented. However, I do recommend the authors consider my earlier suggestions to provide clearer insights as to why semi-empirical methods can sometimes fail badly even for isodesmic reactions. This will spur further research into improving these methods.


Reviewer 3 (Anonymous)

Basic reporting

- Line 132: change "can play and important role" to "can play an important role"

- Citations need to conform to the journal style thoughout: see, e.g., "taken from (Morgenthaler et al., 2007)" in Table 4 caption should be changed to "taken from Morgenthaler et al. (2007)"

- References in the bibliography need to be consistently formatted to journal guidelines

- Other groups have reported validation efforts for predicting pKa values using the PM6 method (see, e.g., Rayne et al. [2009], Juranić [2014], etc.). The authors should cite and incorporate the findings of all these prior PM6 pKa validation efforts into the current study to demonstrate an understanding of the prior literature in this field. Otherwise, it looks as though the authors are attempting to make their research appear more novel than it actually is.

Experimental design

- Experimental design is appropriate.

Validity of the findings

- The findings appear valid.