PropMolFlow: Property-guided Molecule Generation with Geometry-Complete Flow Matching

The paper is now published at Nature Computational Science: "PropMolFlow: Property-guided Molecule Generation with Geometry-Complete Flow Matching", and Demo on an interative website

Dependencies and Setup

Please Make Sure cuda Version >= 12.8 and you have conda installed

Run the following commands in your terminal to set up propmolflow (We have tested the installation on Nvidia L4 and Blackwell B200 GPUs):

conda install mamba # if you do not have mamba
mamba create -n propmolflow python=3.12 nvidia/label/cuda-12.8.1::cuda-toolkit
mamba activate propmolflow
pip install torch==2.7.0 torchvision==0.22.0 torchaudio==2.7.0 --index-url https://download.pytorch.org/whl/cu128
pip install torch-cluster torch_scatter torch_sparse -f https://data.pyg.org/whl/torch-2.7.0%2Bcu128.html
pip install pytorch-lightning==2.5.2
pip install networkx==3.1
pip install einops==0.8.1 rdkit==2025.3.5 py3Dmol==2.5.2 useful-rdkit-utils==0.90
pip install torchtyping ase wandb posebusters 
mamba install -c dglteam/label/th24_cu124 dgl=2.4.0.th24.cu124
pip install -e .

Or you can simply install all packages by

# make sure clone the repo first, and cd PropMolFlow, so conda can run "pip install -e ." without error
conda env create -f environment.yml

Note: The original PropMolFlow work was developed using Nvidia A100-SXM4 and 2080Ti graphic cards. However, as we prepared the github repo, University of Florida has completed retired these A100 and 2080Ti graphic cards, and switched to L4 and B200 cards.

Datasets

QM9 SDF File

We provide a corrected version of the QM9 SDF file originally from DeepChem, fixing issues such as invalid bond orders and non-zero net charges in approximately 30,000 molecules. The SDF data fixing pipeline and its documentation is now included in the folder propmolflow/sdf_data_fix.

To download the revised SDF file, run:

wget https://zenodo.org/records/15700961/files/all_fixed_gdb9.zip
unzip all_fixed_gdb9.zip
rm all_fixed_gdb9.zip

After downloading, move the all_fixed_gdb9.sdf file to the data/qm9_raw/ directory:

mv all_fixed_gdb9.sdf data/qm9_raw/

Note: The SDF file all_fixed_gdb9.sdf (Zenodo version 1), equivalently released as rQM9_v0.sdf (Zenodo version 3), was used to train models in the PropMolFlow study. It is based on an earlier version of the data-fix pipeline and contains 935 problematic molecules, many of which can be corrected using the updated pipeline described in the paper supplementary information. In contrast, the latest version of the pipeline reduces this number to 303 problematic molecules and is available on Zenodo version 3 and HuggingFace ColabFit rQM9. The revised SDF files preserve the original molecule count and ordering to ensure consistency with the order of the property-value CSV file. Therefore, users should remove the provided problematic indices prior to training to ensure data consistency.

The property MAE and structural validity results trained on rQM9_v1.sdf with indices in problematic_indices_v1.npy removed and top-1 property embedding methods trained on the rQM9_v0.sdf file can be found in the data/rQM9_v1_SDF_results folder. Compared to the paper results trained on rQM9_v0.sdf, the structural validities are slightly higher (better), whereas the property MAEs are slightly higher too (worse). Afterall, conclusions in the paper hold. Moleculars indices for training generative PropMolFlow model and the GVP regressors are provided in the data/qm9_raw folder for both sdf versions.

CSV File for Properties

The property-value CSV file is provided in data/qm9_raw directory.

Training

Note: Before training the PropMolFlow generative model, preprocess the all_fixed_gdb9.sdf or rQM_v0.sdf data first, the yaml configuration file can be arbitrary as long as it contains correct raw data paths and filenames:

python process_qm9_cond.py --config=configs/with_gaussian_expansion/alpha_concatenate_multiply.yaml

Note: current procedure removes around 700 molecules that do not pass RDKit sanitization and there are however a very small number of remaining problematic molecules (~200 molecules). All unfixed molecule indices are provided in the problematic_indices_v0.npy for rQM_v0.sdf and problematic_indices_v1.npy for rQM_v1.sdf files, available on the zenodo repo version 3 or in the data/qm9_raw folder,

To use the rQM_v1.sdf data, change the input sdf file to rQM9_v1.sdf in process_qm9_cond.py and skip the identified problematic indices by:

python process_qm9_cond.py --config=configs/with_gaussian_expansion/alpha_concatenate_multiply.yaml --ids_to_skip_file data/qm9_raw/problematic_indices_v1.npy

Then run the train.py script. You can either pass a config file, or pass a model checkpoint to continue training.

# training from scratch
python train.py --config=configs/without_gaussian_expansion/alpha_sum.yaml

# continue training from checkpoints
python train.py --resume=checkpoints/in-distribution/alpha/epoch=1845-step=721785.ckpt --config=configs/without_gaussian/alpha_sum.yaml

The model checkpoints will be saved in runs_qm9_valid folder, you can modify the output dir by changing the output_dir argument in the config file.

Inference

PropMolFlow Checkpoints

Note: We provide 12 model checkpoints with the lowest Mean Absolute Error (MAE) values for 6 molecular properties by pretrained regressor prediction, covering both in-distribution and out-of-distribution tasks. These models are trained on the rQM9_v0.sdf.

To download and extract them, run:

wget https://zenodo.org/records/15700961/files/checkpoints.tar
tar -xvf checkpoints.tar
rm checkpoints.tar

Details on how properties are incorporated into the model (e.g., whether Gaussian expansion was used) can be found in the following files:

• data/property_mae_results/in_distribution_best_combo.csv
• data/property_mae_results/out_of_distribution_best_combo.csv

Note: We also provide all 180 model checkpoints, representing various combinations of property handling methods and Gaussian expansion settings. 

The full benchmark results can be found in:

• data/property_mae_results/in_distribution_full_results.csv
• data/property_mae_results/out_of_distribution_full_results.csv

To download the complete set of checkpoints, run:

wget https://zenodo.org/records/15700961/files/with_gaussian.tar
tar -xvf with_gaussian.tar
rm with_gaussian.tar

wget https://zenodo.org/records/15700961/files/without_gaussian.tar
tar -xvf without_gaussian.tar
rm without_gaussian.tar

Regressor Checkpoints

Note: PropMolFlow does not use EGNN from the EDM (Equivariant Diffuison Model) work for molecular property prediction.
To be self-consistent, we employ Geometric Vector Perceptrons (GVP) as the backbone GNN model of PropMolFlow for the property regressor.

The pre-trained GVP model checkpoints are already included in the repository under:
propmolflow/property_regressor/model_output

There is no need to download them separately.

Note: To train a GVP regressor by yourself, please run:

python propmolflow/property_regressor/train_regressor.py --config=propmolflow/property_regressor/configs/regressor_alpha.yaml 

The trained model will be saved in path propmolflow/property_regressor/model_output.

Demo

Sampling (Generate 3D molecules conditioning on properties)

In-distribution sampling (sampling from the training data joint distribution of # Atoms and property values, p(n, c))

# alpha
python sample_condition.py --model_checkpoint "checkpoints/in-distribution/alpha/epoch=1845-step=721785.ckpt" --n_mols 10000 --max_batch_size 128 --n_timesteps 100 --properties_handle_method "sum" --multilple_values_file "sampling_input/in_distribution_sampling/train_half_sampled_values_alpha.npy" --number_of_atoms "sampling_input/in_distribution_sampling/train_half_sampled_no_atoms_alpha.npy" --property_name "alpha" --normalization_file_path "data/qm9/train_data_property_normalization.pt" --output_file "sampling_input/example_sample_result/alpha_in.sdf" --analyze

# cv
python sample_condition.py --model_checkpoint "checkpoints/in-distribution/cv/epoch=1735-step=678541.ckpt" --n_mols 10000 --max_batch_size 128 --n_timesteps 100 --properties_handle_method "sum" --multilple_values_file "in_distribution_sampling/train_half_sampled_values_cv.npy" --number_of_atoms "in_distribution_sampling/train_half_sampled_no_atoms_cv.npy" --property_name "cv" --normalization_file_path "data/qm9/train_data_property_normalization.pt" --output_file "sampling_input/example_sample_result/cv_in.sdf" --analyze

# gap
python sample_condition.py --model_checkpoint "checkpoints/in-distribution/gap/epoch=1867-step=730387.ckpt" --n_mols 10000 --max_batch_size 128 --n_timesteps 100 --properties_handle_method "concatenate_sum" --multilple_values_file "in_distribution_sampling/train_half_sampled_values_gap.npy" --number_of_atoms "in_distribution_sampling/train_half_sampled_no_atoms_gap.npy" --property_name "gap" --normalization_file_path "data/qm9/train_data_property_normalization.pt" --output_file "sampling_input/example_sample_result/gap_in.sdf" --analyze

# homo
python sample_condition.py --model_checkpoint "checkpoints/in-distribution/homo/epoch=1927-step=753691.ckpt" --n_mols 10000 --max_batch_size 128 --n_timesteps 100 --properties_handle_method "concatenate" --multilple_values_file "in_distribution_sampling/train_half_sampled_values_homo.npy" --number_of_atoms "in_distribution_sampling/train_half_sampled_no_atoms_homo.npy" --property_name "homo" --normalization_file_path "data/qm9/train_data_property_normalization.pt" --output_file "sampling_input/example_sample_result/homo_in.sdf" --analyze

# lumo
python sample_condition.py --model_checkpoint "checkpoints/in-distribution/lumo/epoch=1930-step=754942.ckpt" --n_mols 10000 --max_batch_size 128 --n_timesteps 100 --properties_handle_method "concatenate_sum" --multilple_values_file "in_distribution_sampling/train_half_sampled_values_lumo.npy" --number_of_atoms "in_distribution_sampling/train_half_sampled_no_atoms_lumo.npy" --property_name "lumo" --normalization_file_path "data/qm9/train_data_property_normalization.pt" --output_file "sampling_input/example_sample_result/lumo_in.sdf" --analyze

# mu
python sample_condition.py --model_checkpoint "checkpoints/in-distribution/mu/epoch=1868-step=730778.ckpt" --n_mols 10000 --max_batch_size 128 --n_timesteps 100 --properties_handle_method "multiply" --multilple_values_file "in_distribution_sampling/train_half_sampled_values_mu.npy" --number_of_atoms "in_distribution_sampling/train_half_sampled_no_atoms_mu.npy" --property_name "mu" --normalization_file_path "data/qm9/train_data_property_normalization.pt" --output_file "sampling_input/example_sample_result/mu_in.sdf" --analyze

Out-of-distribution sampling (sampling by a given single value)

# alpha
python sample_condition.py --model_checkpoint "checkpoints/out-of-distribution/alpha/epoch=1845-step=721785.ckpt" --n_mols 1000 --max_batch_size 128 --n_timesteps 100 --properties_handle_method "sum" --properties_for_sampling 93.3 --number_of_atoms "sampling_input/out_of_distribution_sampling/ood_n_atoms_alpha.npy" --property_name "alpha" --normalization_file_path "data/qm9/train_data_property_normalization.pt" --output_file "sampling_input/example_sample_result/alpha_out.sdf" --analyze

# cv
python sample_condition.py --model_checkpoint "checkpoints/out-of-distribution/cv/epoch=1735-step=678541.ckpt" --n_mols 1000 --max_batch_size 128 --n_timesteps 100 --properties_handle_method "sum" --properties_for_sampling 41.2 --number_of_atoms "sampling_input/out_of_distribution_sampling/ood_n_atoms_cv.npy" --property_name "cv" --normalization_file_path "data/qm9/train_data_property_normalization.pt" --output_file "sampling_input/example_sample_result/cv_out.sdf" --analyze

# gap
python sample_condition.py --model_checkpoint "checkpoints/out-of-distribution/gap/epoch=1637-step=640223.ckpt" --n_mols 1000 --max_batch_size 128 --n_timesteps 100 --properties_handle_method "concatenate" --properties_for_sampling 0.344 --number_of_atoms "sampling_input/out_of_distribution_sampling/ood_n_atoms_gap.npy" --property_name "gap" --normalization_file_path "data/qm9/train_data_property_normalization.pt" --output_file "sampling_input/example_sample_result/gap_out.sdf" --analyze

# homo
python sample_condition.py --model_checkpoint "checkpoints/out-of-distribution/homo/epoch=1468-step=574066.ckpt" --n_mols 1000 --max_batch_size 128 --n_timesteps 100 --properties_handle_method "concatenate_sum" --properties_for_sampling=-0.1757 --number_of_atoms "sampling_input/out_of_distribution_sampling/ood_n_atoms_homo.npy" --property_name "homo" --normalization_file_path "data/qm9/train_data_property_normalization.pt" --output_file "sampling_input/example_sample_result/homo_out.sdf" --analyze

# lumo
python sample_condition.py --model_checkpoint "checkpoints/out-of-distribution/lumo/epoch=1865-step=729605.ckpt" --n_mols 1000 --max_batch_size 128 --n_timesteps 100 --properties_handle_method "concatenate_multiply" --properties_for_sampling 0.091 --number_of_atoms "sampling_input/out_of_distribution_sampling/ood_n_atoms_lumo.npy" --property_name "lumo" --normalization_file_path "data/qm9/train_data_property_normalization.pt" --output_file "sampling_input/example_sample_result/lumo_out.sdf" --analyze

# mu
python sample_condition.py --model_checkpoint "checkpoints/out-of-distribution/mu/epoch=1883-step=736409.ckpt" --n_mols 1000 --max_batch_size 128 --n_timesteps 100 --properties_handle_method "sum" --properties_for_sampling 6.74 --number_of_atoms "sampling_input/out_of_distribution_sampling/ood_n_atoms_mu.npy" --property_name "mu" --normalization_file_path "data/qm9/train_data_property_normalization.pt" --output_file "sampling_input/example_sample_result/mu_out.sdf" --analyze

Sampling Arguments Explanation

• model_checkpoint: Path to the trained model checkpoint.
• n_mols: Number of molecules to generate.
• max_batch_size: Batch size used during sampling.
• n_timesteps: Number of integration steps for the ODE solver.
• properties_handle_method: Method for incorporating property values into the model.
  Choices: 'concatenate', 'sum', 'multiply', 'concatenate_sum', 'concatenate_multiply'.
• number_of_atoms: Since property values are often correlated with the number of atoms
  (e.g., molecules with higher heat capacity often contain more atoms),
  we will explain how this is handled in the following section.
• property_name: Property to condition on.
  Choices: 'alpha', 'cv', 'gap', 'homo', 'lumo', 'gap'.
  These six properties are selected to allow fair comparison with previous works.
• multiple_values_file: Path to a .npy file containing multiple property values
  for sampling in in-distribution tasks. The model will generate multiple molecules conditioned on different values.
• properties_for_sampling: A single target value to use for out-of-distribution sampling.
  The model will generate multiple molecules conditioned on the same single value.
• normalization_file_path: Path to the normalization statistics file. It is used for models without Gaussian expansion.
• output_file: Output directory path to save generated molecules.
• analyze: Whether to analyze the validity and stability of the generated molecules.

In-Distribution task

This section explains how to generate the files required for the number_of_atoms and multiple_values_file arguments.

To generate these files, run:

python str2prop_sampler.py

If you want to change the number of molecules generated or the output path, please refer to the configurable arguments inside str2prop_sampler.py.

Property Evaluation

After sampling, we use pre-trained regressors as detailed in Regressor Checkpoints section to predict molecular properties and evaluate the results by comparing the MAE between the input target values and the predicted values for raw generated molecules. Each property has its own pretrained prediction model.

The prediction results will be saved in the prediction_result/ directory.

To run in-distribution prediction and calculate MAE, use the following command:

# this is for in-distribution prediction for alpha and calculate MAE values
# when need to evalute other property value, please modify --checkpoint, --input, --output, --properties_values, --property_name 
python propmolflow/property_regressor/test_regressor.py --checkpoint=propmolflow/property_regressor/model_output/alpha/checkpoints/gvp-regressor-epoch=358-val_loss=0.0061.ckpt --config=propmolflow/property_regressor/configs/test.yaml --input=sampling_input/example_sample_result/example_alpha_in.sdf --output=example_case_alpha_in.pt --properties_values=in_distribution_sampling/train_half_sampled_values_alpha.npy --property_name=alpha

# for other properties such as cv, evalution step is following:
python propmolflow/property_regressor/test_regressor.py --checkpoint=propmolflow/property_regressor/model_output/cv/checkpoints/gvp-regressor-epoch=998-val_loss=0.0027.ckpt --config=propmolflow/property_regressor/configs/test.yaml --input=sampling_input/example_sample_result/example_cv_in.sdf --output=example_case_cv_in.pt --properties_values=in_distribution_sampling/train_half_sampled_values_cv.npy --property_name=cv

Note: For out-of-distribution sampling condition on alpha value, a single value is specified --properties_values argument:

# when need to evalute other property value, please modify --checkpoint, --input, --output, --properties_values, --property_name 
python propmolflow/property_regressor/test_regressor.py --checkpoint=propmolflow/property_regressor/model_output/alpha/checkpoints/gvp-regressor-epoch=358-val_loss=0.0061.ckpt --config=propmolflow/property_regressor/configs/test.yaml --input=sampling_input/example_sample_result/example_alpha_out.sdf --output=example_case_out.pt --properties_values=93.3 --property_name=alpha

These specific property values for the out-of-distribution task are chosen as the 99th quantile of rQM9 training data. They are provided in out_of_distribution_sampling/chosen_target_values.json for different properties. This json file can be generated by running str2prop_sampler.py.

DFT evaluation

To generate the DFT jobs using Gaussian for a generated SDF file, please use the script in propmolflow/utils/generate_dft_submission.py

Use custom datasets

To use your own dataset, please follow the steps in folder CustomDataset.

Citation

If you find this work useful, please cite the following paper:

@article{zeng_propmolflow_2026,
	title = {{PropMolFlow}: property-guided molecule generation with geometry-complete flow matching},
	copyright = {2026 The Author(s), under exclusive licence to Springer Nature America, Inc.},
	issn = {2662-8457},
	shorttitle = {{PropMolFlow}},
	url = {https://www.nature.com/articles/s43588-025-00946-y},
	doi = {10.1038/s43588-025-00946-y},
	language = {en},
	urldate = {2026-01-21},
	journal = {Nature Computational Science},
	publisher = {Nature Publishing Group},
	author = {Zeng, Cheng and Jin, Jirui and Ambrose, Connor and Karypis, George and Transtrum, Mark and Tadmor, Ellad B. and Hennig, Richard G. and Roitberg, Adrian and Martiniani, Stefano and Liu, Mingjie},
	month = jan,
	year = {2026},
	keywords = {Cheminformatics, Computational science},
	pages = {1--10},
}

Acknowledgements

PropMolFlow builds upon the source code from FlowMol. We sincerely thank the authors of FlowMol for their excellent work.