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⚠️ Disclaimer: This repository is deprecated and only meant for reproduction of the published results of G-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.

G-SchNet

Implementation of G-SchNet - a generative model for 3d molecular structures - accompanying the paper "Symmetry-adapted generation of 3d point sets for the targeted discovery of molecules" published at NeurIPS 2019.

G-SchNet generates molecules in an autoregressive fashion, placing one atom after another in 3d euclidean space. The model can be trained on data sets with molecules of variable size and composition. It only uses the positions and types of atoms in a molecule, needing no bond-based information such as molecular graphs.

The code provided in this repository allows to train G-SchNet on the QM9 data set which consists of approximately 130k small molecules with up to nine heavy atoms from fluorine, oxygen, nitrogen, and carbon. We provide the pre- and post-processing routines used in our paper's experiments with QM9 molecules in order to make our results reproducible. Although the code and the following guide is very much tailored to QM9, we also provide a few template scripts with basic functionality that can serve as a solid starting point for the application of G-SchNet to other data sets with differently composed molecular structures. The corresponding description can be found at the bottom of this readme after the introduction to the QM9 scripts.

Requirements

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

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

conda create -n gschnet 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 gschnet
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.

Getting started with G-SchNet and QM9

Clone the repository into your folder of choice:

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

Training a model

A model with the same settings as described in the paper can be trained by running gschnet_script.py with standard parameters:

python ./G-SchNet/gschnet_script.py train gschnet ./data/ ./models/gschnet/ --split 50000 5000 --cuda

The training data (QM9) is automatically downloaded and preprocessed if not present in ./data/ and the model will be stored in ./models/gschnet/. With --split 50000 5000, 50k molecules are used as the training set, 5k are used for validation, and the remaining structures are left out as a test set. 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).

At the bottom of this page, we provide a model trained exactly as described above for download. Feel free to use it instead of training your own model.

Generating molecules

Running the script with the following arguments will generate 1000 molecules using the trained model at ./model/geschnet/ and store them in ./model/gschnet/generated/generated.mol_dict:

python ./G-SchNet/gschnet_script.py generate gschnet ./models/gschnet/ 1000 --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).

Filtering and analysis of generated molecules

After generation, the generated molecules can be filtered for invalid and duplicate structures by running qm9_filter_generated.py:

python ./G-SchNet/qm9_filter_generated.py ./models/gschnet/generated/generated.mol_dict --train_data_path ./data/qm9gen.db --model_path ./models/gschnet

The script will print its progress and the gathered results. To store them in a file, please redirect the console output to a file (e.g. ./results.txt) and use the --print_file argument when calling the script:

python ./G-SchNet/qm9_filter_generated.py ./models/gschnet/generated/generated.mol_dict --train_data_path ./data/qm9gen.db --model_path ./models/gschnet --print_file >> ./results.txt

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/gschnet/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, see tables below for an overview showing all stored statistics).

*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 and QM9 training data molecules

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

python ./G-SchNet/display_molecules.py --data_path ./models/gschnet/generated/generated_molecules.db

The script allows to query the generated molecules for structures with certain properties using --select "selection string". The selection string has the general format "Property,OperatorTarget" (e.g. "C,>8" to filter for all molecules with more than eight carbon atoms where "C" is the statistic counting the number of carbon atoms in a molecule, ">" is the operator, and "8" is the target value). Multiple conditions can be combined to form one selection string using "&" (e.g "C,>8&R5,>0" to get all molecules with more than 8 carbon atoms and at least 1 ring of size 5). Furthermore, multiple selection strings may be provided such that multiple windows with molecule plots are opened (one per selection string). The available operators are "<", "<=", "=", "!=", ">=", and ">". Properties may be summed together using "+" (e.g. "R5+R6,=1" to get molecules with exactly one ring of size 5 or 6). For a list of all available properties, see the tables below.

An example call to display all generated molecules that consist of at least 7 carbon atoms and two rings of size 6 or 5 and to display all generated molecules that have at least 1 Fluorine atom:

python ./G-SchNet/display_molecules.py --data_path ./models/gschnet/generated/generated_molecules.db --select "C,>=7&R5+R6,=2" "F,>=1"

The same script can also be used to display molecules from the QM9 training database using --train_data_path:

python ./G-SchNet/display_molecules.py --train_data_path ./data/qm9gen.db

Note that displaying all ~130k molecules from the database is quite slow. However, the training database can also be queried in a similar manner by prepending "training" to the selection string. For example, the following call will display all molecules from the QM9 database that have at least one Fluorine atom and not more than 5 other heavy atoms:

python ./G-SchNet/display_molecules.py --train_data_path ./data/qm9gen.db --select "training F,>=1&C+N+O,<=5"

Using --train or --test with --data_path will display all generated molecules that match structures used for training or held out test data, respectively, and the corresponding reference molecules from the QM9 database if --train_data_path is also provided. --novel will display all generated molecules that match neither structures used for training nor held out test data.

The indices of molecules matching the queries can be exported using --export_to_dir. For example, the indices of all molecules from QM9 with HOMO-LUMO gap < 4.5 eV will be stored as numpy-readable file training gap,<=4.5.npy at ./data/subsets/ by calling:

python ./G-SchNet/display_molecules.py --train_data_path ./data/qm9gen.db --select "training gap,<=4.5" --export_to_dir ./data/subsets

The following properties are available for both generated molecules as well as structures in the QM9 training database:

Additionally, generated molecules allow to use the following properties in selection strings:

Finally, molecules from the QM9 training database can also be queried for properties available in the QM9 data set:

All properties use the ASE-internal units and therefore can easily be converted with ASE. For example, you can get the dipole moment in Debye by multiplying it with 1/ase.units.Debye. Similarly, the isotropic polarizability can be converted to Bohr³ using 1/ase.units.Bohr³ and the electronic spatial extent may be obtained in Bohr² with 1/ase.units.Bohr².

Training a biased model

The generation of molecules with G-SchNet can be biased towards desired target properties of QM9 molecules. To this end, the weights of an already trained model are fine-tuned in a second training run where only a small number of molecules that exhibit the desired target property is used as training data. For example, we biased the generation towards molecules with a small HOMO-LUMO gap in our paper. We found that the pre-training with a large and diverse set of molecules would increase the robustness of the learned model (e.g. increase the number of generated molecules that are valid structures) compared to training on the small subset directly.

The second training run for biasing is started with the same script as the usual training but requires two additional parameters. This is the path to an already trained model that is used to initialize the weights and the path to a file holding the indices of molecules that exhibit the desired target property. Such a file can be obtained using the display_molecules script (see description in the section above, where we extract the indices of all molecules with HOMO-LUMO gap smaller than 4.5 eV).

Assume there is a model already trained on 50k examples from QM9 at ./models/gschnet and a file with the indices of 3000 molecules that exhibit the desired target property at ./data/subsets/indices.npy, then a biased model can be trained with the following call:

python ./G-SchNet/gschnet_script.py train gschnet ./data/ ./models/biased_gschnet/ --split 2000 500 --cuda --pretrained_path ./models/gschnet --subset_path ./data/subsets/indices.npy

The argument --split needs to be adjusted according to the number of molecules available in the subset. Note that the learning rate parameters can also be adjusted with --lr, --lr_decay, --lr_patience, and --lr_min, which are 1e-4, 0.5, 10, and 1e-6 per default, respectively. In our paper, we used these standard parameters for the pre-training as well as for the fine-tuning with respect to small HOMO-LUMO gaps, where we had 3.3k molecules for training and 0.5k for validation. If there are significanly less molecules exhibiting the target property, it could be better to decrease the learning rate for the fine-tuning step such that overfitting is prevented as more information from the pre-trained weights is retained. On the contrary, if there is a larger subset of molecules with the target property, training G-SchNet directly on that subset might lead to similarly good results as starting from the pre-trained weights.

After the training has converged, molecules can be sampled from the biased distribution and filtererd afterwards just as before and described in the previous sections (but of course the path to the model directory ./models/geschnet needs to be replaced with ./models/biased_gschnet in the arguments when calling the scripts).

Applying G-SchNet to other data sets

Disclaimer: Since the code was mainly written to run experiments on QM9, experiments with other data sets will most likely need code adaptations. Although G-SchNet generalizes well to larger structures in theory, there are a few key points missing in the current implementation that might hinder its applicability to structures with many atoms (e.g. significantly more than 100). For example, all already placed atoms are predicting a distance to the new position at each step right now. Here it would be better to introduce a cutoff that limits the number of atoms used to predict distances to a smaller region around the focus token. Furthermore, we currently also do not use the provided cutoff to limit the number of neighbors that are examined in the SchNet feature extraction (i.e. we always use the full distance matrix in the continuous filter convolutions instead of removing atoms from the computations that are masked by the cutoff anyways). Therefore, we recommend to instead use our re-implementation of G-SchNet which uses such cutoffs and is designed to work with larger molecules and custom data.

In the following we will describe the provided template scripts and how they could be adjusted in order to use our implementation of G-SchNet on data sets other than QM9. There are three relevant files, template_data.py, template_preprocess_dataset.py, and template_filter_generated.py. They take care of loading the data, pre-processing the data, and filtering molecules after generation, respectively.

Adjusting the template data class

The file template_data.py contains a template data class that loads molecules from an sq-lite database assembled with ASE. It already provides all the necessary functionality to run with gschnet_script.py (e.g. using only subsets of data, splitting of the data set, initialisation of pre-processing etc.). However, a few basic properties of the used data set must be coded as static class variables that can be found at the top of the class definition. These are the name of the original data base file (db_name), the desired name of the data base file after pre-processing (preprocessed_db_name), a list of all the atom types that occur in the data base (available_atom_types), the valence constraints of these types (atom_types_valence, currently not used, can safely be set to None), and the minimum and maximum distance between two atoms that are considered as neighbors for the data set (radial_limits). Note that the setting for the radial_limits here will determine which atoms are considered to be connected when calculating connectivity matrices during pre-processing as well as the extent of the radial grid around the focus token used during generation.

Pre-processing of data

The file template_preprocess_dataset.py contains functions for very basic pre-processing of the data set. In contrast to the procedure that we implemented for QM9, we do not check for valency constraints here as this can get very complicated when allowing other atom types than those in QM9. Furthermore, the detection of bonds with Open Babel is not very reliable, especially for kekulization of aromatic structures containing nitrogen and carbon atoms. We provided heuristics to compensate the shortcomings of the Open Babel implementation for QM9 molecules but cannot guarantee that they lead to any meaningful results when using substantially different molecular structures. Thus, one would need to implement an own strategy for valency checks if desired when using data sets other than QM9.

The provided script only uses the limits specified under radial_limits in template_data.py to determine which atoms in a molecule are connected and stores the calculated connectivity matrices in the target data base in a compressed format. As our generation procedures places new atoms only in the proximity of the focused atom, it is required that every pair of atoms in a molecule is connected by some path. Otherwise, the algorithm would not be able to generate the structure since there are disconnected parts that cannot be reached. Thus we remove such disconnected structures. If you encounter a lot of removals due to disconnectedness, you should consider increasing the maximum value in radial_limits in the template data class.

Filtering generated molecules

Finally, the script template_filter_generated.py can be used to filter molecules after generation. As a simple filter example, we remove generated molecules where two atoms are closer than 0.3 Ångström since we consider them to be invalid.The script then only stores generated molecules in an ase sq-lite data base such that they can be visualized with the display_molecules.py script and also generates a statistics file that includes very basic statistics (i.e. the number of atoms of a certain type). All other, more sophisticated filtering routines need to be implemented according to the specific data set and experimental setup. This could for example be valency checks or identification of duplicate molecules. Again, we removed our implementation of those routines for QM9 as they cannot be easily generalized to arbitrarily composed molecules.

Initialize training on custom data set

After adding the required arguments to the data class in template_data.py and, optionally, implementing further routines for pre-processing of the data set or filtering of generated molecules, you can start training G-SchNet on your data set by adding --dataset_name template_data to the training call:

python ./G-SchNet/gschnet_script.py train gschnet ./data/ ./models/gschnet_my_data/ --dataset_name template_data --split 2000 200 --cuda

Do not forget to adjust the number of training and validation molecules according to your data set with --split #train_samples #val_samples (2000 and 200 in the example call above). In order to generate 1000 molecules and filter them afterwards, simply use the following calls:

python ./G-SchNet/gschnet_script.py generate gschnet ./models/gschnet_my_data/ 1000 --cuda
python ./G-SchNet/template_filter_generated.py ./models/gschnet_my_data/generated/generated.mol_dict

The filtered molecules can then be viewed with ASE:

ase gui ./models/gschnet_my_data/generated/generated_molecules.db    

Tweaking model and batch sizes

For training on data sets with large molecules or when using a GPU with less than 16GB VRAM there are a few parameters that can be tweaked to manage the model and batch sizes. We recommend to lower the number of interaction layers in the features extraction part using e.g. --interactions 6 (default is 9) or to lower the number of features to e.g. --features 64 (default is 128). Furthermore, the number of molecules considered per batch can be lowered using e.g. --batch_size 2 (default is 5). However, the size of the batches does also depend on the number of atoms in molecules of the batch as G-SchNet is an autoregressive model that predicts each atom placement step individually. In the default setup, we always sample a complete atom placement trajectory for each molecule of the batch, which means that batch sizes will become very large for molecules with many atoms. To mitigate this problem, you can set e.g. --draw_random_samples 10 to draw ten atom placement steps for each molecule in the batch randomly instead of sampling the whole trajectory. In this way, it should be possible to train G-SchNet on larger molecules than those in QM9 even though the cutoffs are not properly implemented yet (as explained in the disclaimer above).

If you need help to train G-SchNet on your own data, don't hesitate to open an issue or drop us an e-mail.

Citation

If you are using G-SchNet in your research, please cite the corresponding paper:

N. Gebauer, M. Gastegger, and K. Schütt. Symmetry-adapted generation of 3d point sets for the targeted discovery of molecules. In H. Wallach, H. Larochelle, A. Beygelzimer, F. d'Alché-Buc, E. Fox, and R. Garnett, editors, Advances in Neural Information Processing Systems 32, pages 7566–7578. Curran Associates, Inc., 2019.

@incollection{NIPS2019_8974,
title = {Symmetry-adapted generation of 3d point sets for the targeted discovery of molecules},
author = {Gebauer, Niklas and Gastegger, Michael and Sch\"{u}tt, Kristof},
booktitle = {Advances in Neural Information Processing Systems 32},
editor = {H. Wallach and H. Larochelle and A. Beygelzimer and F. d\textquotesingle Alch\'{e}-Buc and E. Fox and R. Garnett},
pages = {7566--7578},
year = {2019},
publisher = {Curran Associates, Inc.},
url = {http://papers.nips.cc/paper/8974-symmetry-adapted-generation-of-3d-point-sets-for-the-targeted-discovery-of-molecules.pdf}
}

Trained G-SchNet model

Here we provide an already trained G-SchNet model ready to be used for molecule generation or further fine-tuning and biasing. The model was trained as described in the paper, using the standard settings of the gschnet_script and 50k structures from QM9 (as explained in "Training a model" above). Simply extract the folder "gschnet" from the provided zip-file into ./models and continue with the steps described in "Generating molecules" or "Training a biased model" from the guide above. We used an environment with pytorch 1.5.0, cudatoolkit 10.2, and schnetpack 0.3 for training.

Download here.

The QM9 training data is usually downloaded and pre-processed as a first step of the training script. If you use our trained model from here instead of training your own model, you might still need the training data (e.g. for visualization or filtering of generated molecules). In this case, you can simply start a dummy training with zero epochs to initialize the data download and remove the dummy model afterwards:

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