Conformer energy minimization with Openforcefield #OpenFF #RDKit

Last month, I posted topics about conformer generation code with rdkit.

https://iwatobipen.wordpress.com/2021/01/31/generate-conformers-script-with-rdkit-rdkit-chemoinformatics/
https://github.com/iwatobipen/rdk_confgen

RDK_confgen can generate multiple conformers from molfile. This code generates conformers with MMFF94s forcefield. On the other hand recently open force field is very attractive package for these are I think.

Fortunately OpenFF provides example code for conformer energy minimization as CLI tool. So I tested the code.

At first, I made sample molecule for the test.

# from IPython console
from rdkit import Chem
mol = Chem.MolFromSmiles('C1CN2C(=NN=C2C(F)(F)F)CN1C(=O)C[C@@H](CC3=CC(=C(C=C3F)F)F)N')
Chem.MolToMolFile(mol, 'januvia.mol')

Then generate conformers with rdk_confgen. After running the code, I could obtain januvia.sdf which has 10 conformers of input molfile.

$ confgen -i januvia.mol -o januvia.sdf --numconf 10

Now ready, run conformer energy minimization code which is provided from openFF github repo. The URL is below.

https://github.com/openforcefield/openff-toolkit/blob/de8a4a545351301adfe424dff0d879b2dd13bc0b/examples/conformer_energies/conformer_energies.py

Down load the example script and type following command. I don’t have OE licence so rdkit is used as backend.

$ python conformer_energies.py -f januvia.sdf
Warning: Unable to load toolkit 'OpenEye Toolkit'. The Open Force Field Toolkit does not require the OpenEye Toolkits, and can use RDKit/AmberTools instead. However, if you have a valid license for the OpenEye Toolkits, consider installing them for faster performance and additional file format support: https://docs.eyesopen.com/toolkits/python/quickstart-python/linuxosx.html OpenEye offers free Toolkit licenses for academics: https://www.eyesopen.com/academic-licensing
1 unique molecule(s) loaded, with 10 total conformers
C16H15N5O1F6 : 10 conformers
Parametrizing C16H15N5O1F6 (may take a moment to calculate charges)
Conformer         Initial PE         Minimized PE       RMS between initial and minimized conformer
    1 /    10 :  133.220 kcal/mol  123.417 kcal/mol     0.567 Angstroms
    2 /    10 :  134.822 kcal/mol  125.368 kcal/mol     0.123 Angstroms
    3 /    10 :  136.633 kcal/mol  126.529 kcal/mol     0.343 Angstroms
    4 /    10 :  136.635 kcal/mol  126.519 kcal/mol     0.365 Angstroms
    5 /    10 :  135.224 kcal/mol  125.566 kcal/mol     0.303 Angstroms
    6 /    10 :  135.214 kcal/mol  125.556 kcal/mol     0.307 Angstroms
    7 /    10 :  137.509 kcal/mol  127.497 kcal/mol     0.618 Angstroms
    8 /    10 :  135.326 kcal/mol  125.955 kcal/mol     0.153 Angstroms
    9 /    10 :  137.716 kcal/mol  127.200 kcal/mol     0.621 Angstroms
   10 /    10 :  138.217 kcal/mol  128.632 kcal/mol     0.184 Angstroms

After running the code, minimized structures from each conformer was generated as 10 SD files. Running results said that initial structure has higher energy than optimized structure. Here is an example of the result. Purple is an initial structure and green one is optimized.

OpenFF provides some kinds of offxml files https://github.com/openforcefield/openff-forcefields/tree/master/openforcefields/offxml

So I would like to test with different settings and compare results with bio active conformations.

And I would like to know how to run simulate small molecule in solvent with OpenFF. OpenMM can do it but I couldn’t find solution to combine openff forcefiled and openmm forcefiled for solvent such as TIP3P. I’m reading OpenMM document now.

Any comments, advise will be greatly appreciated. ;)

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Published by iwatobipen

I'm medicinal chemist in mid size of pharmaceutical company. I love chemoinfo, cording, organic synthesis, my family.

2 thoughts on “Conformer energy minimization with Openforcefield #OpenFF #RDKit

  1. And I would like to know how to run simulate small molecule in solvent with OpenFF. OpenMM can do it but I couldn’t find solution to combine openff forcefiled and openmm forcefiled for solvent such as TIP3P. I’m reading OpenMM document now.

    OpenFF received a user’s code snippet that does exactly this yesterday… Maybe from one of your readers! https://github.com/openforcefield/openff-toolkit/issues/844

    Also, personally, it’s a huge honor to see OpenFF on your blog. I’ve been a reader for several years, so it’s awesome to see our work make it here :-)

    1. Thank you for your information and comment. I’m really happy to hear that you are reader of this blog! It’s awesome. I respect your great work open FF is useful tool for compound design.
      I’ll try to run the code!

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