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⚠️ Disclaimer: This repository is deprecated and only meant for reproduction of the published results of cG-SchNet on QM9. If you want to use custom data sets or build on top of our model, please refer to the up-to-date implementation.

cG-SchNet - A Conditional Generative Neural Network for 3d Molecules

<a href="https://zenodo.org/badge/latestdoi/434276895"><img src="https://zenodo.org/badge/434276895.svg" alt="DOI"></a>

Implementation of cG-SchNet - a conditional generative neural network for 3d molecular structures - accompanying the paper "Inverse design of 3d molecular structures with conditional generative neural networks". If you are using cG-SchNet in your research, please cite the corresponding publication:

N.W.A. Gebauer, M. Gastegger, S.S.P. Hessmann, K.-R. Müller, and K.T. Schütt.
Inverse design of 3d molecular structures with conditional generative neural networks.
Nature Communications 13, 973 (2022). https://doi.org/10.1038/s41467-022-28526-y

@Article{gebauer2022inverse,
    author={Gebauer, Niklas W. A. and Gastegger, Michael and Hessmann, Stefaan S. P. and M{\"u}ller, Klaus-Robert and Sch{\"u}tt, Kristof T.},
    title={Inverse design of 3d molecular structures with conditional generative neural networks},
    journal={Nature Communications},
    year={2022},
    volume={13},
    number={1},
    pages={973},
    issn={2041-1723},
    doi={10.1038/s41467-022-28526-y},
    url={https://doi.org/10.1038/s41467-022-28526-y}
}

The code provided in this repository allows to train cG-SchNet on the tasks presented in the paper using the QM9 data set which consists of approximately 130k small molecules with up to nine heavy atoms from fluorine, oxygen, nitrogen, and carbon.

We also provide links to the molecules generated with cG-SchNet for the paper as well as two pretrained models used therein. For details, please refer to the folder published_data.

Requirements

• schnetpack 0.3
• pytorch >= 1.2
• python >= 3.7
• ASE >= 3.17.0
• Open Babel 2.41
• rdkit >= 2019.03.4.0

In the following, we describe the setup using Anaconda.

The following commands will create a new conda environment called "cgschnet" and install all dependencies (tested on Ubuntu 18.04 and 20.04):

conda create -n cgschnet python=3.7 pytorch=1.5.1 torchvision cudatoolkit=10.2 ase=3.19.0 openbabel=2.4.1 rdkit=2019.09.2.0 -c pytorch -c openbabel -c defaults -c conda-forge
conda activate cgschnet
pip install 'schnetpack==0.3'

Replace "cudatoolkit=10.2" with "cpuonly" if you do not want to utilize a GPU for training/generation. However, we strongly recommend to use a GPU if available.

To observe the training progress, install tensorboard:

pip install tensorboard

Getting started

Clone the repository into your folder of choice:

git clone https://github.com/atomistic-machine-learning/cG-SchNet.git

Training a model

A model conditioned on the composition of molecules and their relative atomic energy with the same settings as described in the paper can be trained by running gschnet_cond_script.py with the following parameters:

python ./cG-SchNet/gschnet_cond_script.py train gschnet ./data/ ./models/cgschnet/ --conditioning_json_path ./cG-SchNet/conditioning_specifications/4_comp_relenergy.json --split_path ./cG-SchNet/splits/4_comp_relenergy_split.npz --cuda

The training data (QM9) is automatically downloaded and preprocessed if not present in ./data/ and the model will be stored in ./models/cgschnet/. We recommend to train on a GPU but you can remove --cuda from the call to use the CPU instead. If your GPU has less than 16GB VRAM, you need to decrease the number of features (e.g. --features 64) or the depth of the network (e.g. --interactions 6). The conditioning network is specified in a json-file. We provide the settings used in experiments throughout the paper in ./cG-SchNet/conditioning_specifications. The exact data splits utilized in our trainings are provided in ./cG-SchNet/splits/. The conditioning network and corresponding split are numbered like the models in Supplementary Table S1, where we list the hyper-parameter settings. Simply replace the paths behind the --conditioning_json_path and --split_path arguments in order to train the desired model. If you want to train on a new data split, remove --split_path from the call and instead use --split x y to randomly create a new split with x training molecules, y validation molecules, and the remaining molecules in the test set (e.g. with x=50000 and y=5000).

The training of the full model takes about 40 hours on a A100 GPU. For testing purposes, you can leave the training running for only a couple of epochs. An epoch should take 10-20 min, depending on your hardware. To observe the training progress, use TensorBoard:

tensorboard --logdir=./models

The logs will appear after the first epoch has completed.

Generating molecules

Running the script with the following arguments will generate 1000 molecules using the composition C7O2H10 and relative atomic energy of -0.1 as conditions using the trained model at ./model/cgschnet/ and store them in ./model/cgschnet/generated/generated.mol_dict:

python ./cG-SchNet/gschnet_cond_script.py generate gschnet ./models/cgschnet/ 1000 --conditioning "composition 10 7 0 2 0; n_atoms 19; relative_atomic_energy -0.1" --cuda

Remove --cuda from the call if you want to run on the CPU. Add --show_gen to display the molecules with ASE after generation. If you are running into problems due to small VRAM, decrease the size of mini-batches during generation (e.g. --chunk_size 500, default is 1000).

Note that the conditions for sampling are provided as a string using the --conditioning argument. You have to provide the name of the property (as given in the field in_key_property in the conditioning specification json without trailing underscore) followed by the target value(s). Each property the model was conditioned on, i.e. as listed in one of the layers in the conditioning specification json, has to be provided. Otherwise, the target value will be set to zero which often is an inappropriate value and thus may lead to invalid molecules. The composition of molecules is given as the number of atoms of type h, c, n, o, f (in that particular order). When conditioning on fingerprints, the value can either be an index (which is used to load the fingerprint of the corresponding molecule in the ./data/qm9gen.db data base) or a SMILES string.

Filtering and analysis of generated molecules

After generation, the generated molecules can be filtered for invalid and duplicate structures by running filter_generated.py:

python ./cG-SchNet/filter_generated.py ./models/cgschnet/generated/generated.mol_dict --train_data_path ./data/qm9gen.db --model_path ./models/cgschnet

The script will print its progress and the gathered results. The script checks the valency constraints (e.g. every hydrogen atom should have exactly one bond), the connectedness (i.e. all atoms in a molecule should be connected to each other via a path over bonds), and removes duplicates*. The remaining valid structures are stored in an sqlite database with ASE (at ./models/cgschnet/generated/generated_molecules.db) along with an .npz-file that records certain statistics (e.g. the number of rings of certain sizes, the number of single, double, and triple bonds, the index of the matching training/test data molecule etc. for each molecule).

In order to match the generated structures to training/test data, the QM9 data set is required. If it hasn't been downloaded before, e.g. because you are using a pretrained model for generation, you can initialize the download by starting to train a dummy model for zero epochs and deleting it afterwards as follows:

python ./cG-SchNet/gschnet_cond_script.py train gschnet ./data/ ./models/_dummy/ --split 1 1 --max_epochs 0
rm -r ./models/_dummy

*Please note that, as described in the paper, we use molecular fingerprints and canonical smiles representations to identify duplicates which means that different spatial conformers corresponding to the same canonical smiles string are tagged as duplicates and removed in the process. Add '--filters valence disconnected' to the call in order to not remove but keep identified duplicates in the created database.

Displaying generated molecules

After filtering, all generated molecules stored in the sqlite database can be displayed with ASE as follows:

python ./cG-SchNet/display_molecules.py --data_path ./models/cgschnet/generated/generated_molecules.db

How does it work?

cG-SchNet is an autoregressive neural network. It builds 3d molecules by placing one atom after another in 3d space. To this end, the joint distribution of all atoms is factorized into single steps, where the position and type of the new atom depends on the preceding atoms (Figure a). The model also processes conditions, i.e. values of target properties, which enable it to learn a conditional distribution of molecular structures. This distribution allows targeted sampling of molecules that are highly likely to exhibit specified conditions (see e.g. the distribution of the polarizability of molecules generated with cG-SchNet using five different target values in Figure b). The type and absolute position of new atoms are sampled successively, where the probability of the positions is apporximated from predicted pairwise distances to preceding atoms. In order to improve the accuracy of the approximation and steer the generation process, the network uses two auxiliary tokens, the focus and the origin. The new atom always has to be a neighbor of the focus and the origin marks the supposed center of mass of the final structure. A scheme explaining the generation procedure can be seen in Figure c. It uses 2d positional distributions for visualization purposes. For more details, please refer to the publication here.