## Friday, January 26, 2018

### xyz2mol: converting an xyz file to an RDKit mol object

I have written a program called xyzmol that converts an xyz file to an RDKit mol object, based on this paper.  For ions the molecular charge has to be specified in the xyz file.

In principle this could be accomplished by using OpenBabel to convert an xyz file to and sdf file and reading the sdf file with RDKit. However, in my experience OpenBabel occasionally mis-assigns bond orders and I believe this code does this less often.

The code works by constructing an atom connectivity (AC) matrix from the xyz file, converts the AC matrix to a bond order (BO) matrix, computes the formal atomic charges, and then constructs a molecule object using all this information, including the 3D coordinates.

The code that constructs the AC matrix from the xyz file (xyz2AC) uses scaled covalent radii to find bonds and the current scale factor is 1.25, but this may need adjusting.

The code currently works only for organic molecules, i.e. molecules containing the following elements: H, B, C-F, Si-Cl, Br, and I.

The current version assumes a close shell molecule, i.e. it does not work with radicals yet.

I hope you find it useful.

## Tuesday, January 23, 2018

### Open access chemistry publishing options in 2018

I just noticed that my go-to journal increased its APC again.* Now there's a flat fee of $1095 so I am re-evaluating my options for impact neutral OA publishing. I don't think PeerJ is greedy, so I think the most likely explanation is be that their old model was not sustainable. I now feel I have been a bit to hard on some other OA publishers (e.g. here and here, but not here). While price and impact-neutrality is the main consideration, open peer review is a nice bonus that I became accustomed to from PeerJ. In my experience it makes for much better reviews and keeps the tone civil. Impact neutral journals$750 ACS Omega (+ ACS membership $166/year). Closed peer review. WARNING: not real OA. You still sign away your copyright to the ACS.$1000 F1000Research. Open peer review. Bio-related

$1095 PeerJ. Open peer review. Bio-related. PeerJ also has a membership model, which may be cheaper than the APC. (The RSC manages "the journal’s chemistry section by commissioning articles and overseeing the peer-review process")$1350 Cogent Chemistry. Has a "pay what you can" policy. Closed peer review.

$1495 PLoS ONE. Closed peer review.$1760 Scientific Reports. Closed peer review

Free or reasonably priced journals that judge perceived impact
$0 Chemical Science Closed peer review$0 Beilstein Journal of Organic Chemistry. Closed peer review.

$0 Beilstein Journal of Nanotechnology. Closed peer review.$0 ACS Central Science. Closed peer review.

\$100 Living Journal of Computational Molecular Science. Closed peer review

€500 Chemistry2. Closed peer review.

£500 RSC Advances. Closed peer review. (Normally £750)

Let me know if I have missed anything.

## Wednesday, January 17, 2018

### Drug design: My latest paper explained without the jargon

Our latest paper has appeared in the latest issue of Chemical Science. It's ultimately related to making better drugs so first some background.

Background
Making complex drug candidates for testing is usually done in several steps where new chemical groups are added at each step. There are usually several reactive atoms and the challenge is to predict the most reactive one. This is currently done mostly by chemical intuition and related literature examples – an approach that often fails, which contributes significantly to the cost of making new drugs. So, there is a need for a fast, yet powerful and easy-to-use tool to predict the most reactive atom in a molecule.

The New Study
For this study we collaborated with the pharmaceutical company Lundbeck A/S to develop a user-friendly tool to predict the most reactive atoms for one of the most often used chemical reaction within drug design.  We compared our predictions against published results for more than 500 different kinds of molecules and found that we made correct predictions in 96% of the cases.
We have made the software is available free to anyone and also made an easy-to-use web interface at regiosqm.org.  We are now working on extending the method to other types of reactions.

## Saturday, January 13, 2018

### Number of possible fragments for the connectivity-based hierarchy scheme

Faithful readers of this blog (hi, mom!) will know that we have been working with the connectivity-based hierarchy (CBH) approach for a while (paper almost done). The method works by breaking molecules up into fragments and truncating with hydrogens. In the CBH-1 scheme you fragment into bonds (so propane would be fragmented into 2 ethane molecules) and in the CBH-2 scheme you include all bonds to an atom with 2 or more bonds (butane would be fragmented into 2 propane molecules).

I started wondering how many different fragments we would need to cover most organic molecules wth the CBH-2 scheme so I wrote some code (shown below) to find out and the number turns out to be 15,670 neutral molecules using ["C","N","O","F","Si","P","S","Cl","Br","I"]

This number also includes CBH-1 fragments because you need them in the CBH-2 scheme. There are a few special cases missing such as isocyanide and there aren't any rings such as cyclopropane, since these are not made until you get higher up in the CBH hierarchy.  Also, there are some very weird molecules that you'll probably never see as a functional group in an organic molecule.

The code considers all possible combinations (so it runs for a long time) and then uses RDKit to figure out if it's a reasonable molecule.

As mentioned the code only generates neutral molecules, so the actual number of fragments needed will be higher.

## Monday, January 1, 2018

### Planned papers for 2018

A year ago I thought I'd probably publish seven papers in 2017:

Accepted
1. Protein structure refinement using a quantum mechanics-based chemical shielding predictor
2. Prediction of pKa values for drug-like molecules using semiempirical quantum chemical methods

Probable
3. Intermolecular Interactions in the Condensed Phase: Evaluation of Semi-empirical Quantum Mechanical Methods
4. Fast Prediction of the Regioselectivity of Electrophilic Aromatic Substitution Reactions of Heteroaromatic Systems Using Semi-Empirical Quantum Chemical Methods
5. Benchmarking cost vs. accuracy for computation of NMR shielding constants by quantum mechanical methods
6. Improved prediction of chemical shifts using machine learning
7. PM6 for all elements in GAMESS, including PCM interface

As you can see from the links the end result will be three papers, because paper 4, while accepted in 2017, will be officially published in 2018. In addition I also published this short preprint and a proposal.

Here's the plan for 2018

Accepted

Probable
2. Random Versus Systematic Errors in Reaction Enthalpies Computed using Semi-empirical and Minimal Basis Set Methods
3. Improving Solvation Energy Predictions using the SMD Solvation Method and Semi-empirical Electronic Structure Methods

Maybe
4. Towards a barrier height benchmark set for biologically relevant systems - part 2
5. pKaSQM: Automated Prediction of pKa Values for Druglike Molecules Using Semiempirical Quantum Chemical Methods
6. Prediction of CH pKa values

Paper 2 is essentially done and I've blogged about it here and here. I thought Paper 3 was also essentially done, but we discovered that the PM6/SMD geometry optimization has some problems with X-H bond breaking so we have to go back and look at that.  I am still quite confident we will get this out in 2018.

Paper 4: much of the work is done but we haven't started in the manuscript. We have collected 11 new systems to include in the database and we plan to improve the accuracy of the benchmark values using the approach in paper 2.

Paper 5: As I wrote in July: "This paper is 2/3 written and presents a completely automated PM3-based pKa prediction protocol. The method works quite well, but most outliers turn out to be due to high energy conformations. The main remaining issue is to find a conformer-search protocol that consistently gives low-energy conformations. Depending on how much time I have to devote to paper 4 and the proposal mentioned below, I am still hopefull I can get this published this year." You can read more about it here, here, and here.

This was put on the back burner to focus on other things, but we have started to look at the conformation issue again with my new PhD student Mads. It also looks like the accuracy can be improved by using the new PM3/SMD radii from paper 3. My main issue with QM-based pKa prediction is that I am not sure we can ever beat the accuracy of the empirical predictors.

Paper 6: I think it might be more fruitful to focus on CH pKa values since they are of interest to synthetic chemists and there is currently no other predictor that I know of. I have written some prototype code and I am in the process of creating a test set from Bordwell's data as a side project, but the fate of this project is really in the hands of the Danish Science Foundation. I'll know more in the Spring.

Work in progress
I have been working on some prototype codes (here, here, and here) aimed at high throughput screening of barrier heights and Mads will be building on this in 2018.