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SE(3)-Stochastic Flow Matching for Protein Backbone Generation

OT-CFM Preprint pytorch

FoldFlow is a flow matching generative model for protein design. FoldFlow works by generating protein structures as represented on the $SE(3)^N_0$ manifold. We investigate improvements such as including minibatch optimal transport conditional flows (FoldFlow-OT) which greatly improves designability and stochastic paths (FoldFlow-SFM), which increases the proportion of novel designs. For more information see our arXiv preprint.

This code heavily relies on and builds off of the FrameDiff code. We thank the authors of that work for their efforts.

foldflow

Installation

To reproduce our results or train your own models you can install our codebase and its dependencies directly from this repository. The following command will clone our repository, create a conda environment from se3.yml, and install the dependencies. We tested the code with Python 3.9.15, and CUDA 11.6.1.

git clone https://github.com/DreamFold/FoldFlow.git
cd FoldFlow
conda env create -f se3.yml
conda activate se3
pip install -e .

Inference

This project uses hydra for configuration which allows easy command-line overrides and structured configs. You can find all the configurations files in runner/config.

In order to run inference with you own checkpoints or with our pretrained checkpoints, you need to specify the path to the checkpoint in the runner/config/inference.yaml file. During inference, we also evaluate FoldFlow designs using the Protein MPNN and ESMfold.

In runner/config/inference.yaml you can directly add the path to the checkpoints.

inference:
  name: null
  gpu_id: 0  # CUDA GPU to use
  seed: 123
  full_ckpt_dir: None

  # Directory of software, weights, and outputs.
  pt_hub_dir: hub/checkpoints # ESMfold checkpoints
  pmpnn_dir: ./ProteinMPNN/
  output_dir: ./results/ # your output directory

  # Path to model weights.
  weights_path: path/to/ckpt/step_10.pth # Your FoldFlow checkpoint.

Once you have specified the path to the checkpoints, you can run inference using the following command:

python runner/inference.py

this will automatically use the configurations from runner/config/inference.yaml.

You can also modify the configurations from the command line. For example, if you want to change the path to the checkpoint and change the name of the experiment, you can run the following command:

python runner/inference.py inference.weights_path=path/to/new_ckpt.pth inference.name=new_ckpt

We followed the same inference procedure as SE(3) diffusion model with application to protein backbone generation. The results are saved in results/ (or an another path that you specified), in the following way:

results/
    └── inference.name # Name of the experiment, if not specified it will be the time.
        └── length_50 # Length of the protein.
            ├── sample_0 # First FoldFlow design.
            │   ├── bb_traj_1.pdb # x_{t-1} diffusion trajectory.
            │   ├── sample_1.pdb # Sample at the final step.
            │   ├── x0_traj_1.pdb # x_0 model prediction trajectory
            │   ├── self_consistency # Self consistency results.
            │   │   ├── esmf # ESMFold predictions using ProteinMPNN sequences.
            │   │   │   ├── sample_0.pdb
            │   │   ├── parsed_pdbs.jsonl # Parsed chains for ProteinMPNN
            │   │   ├── sample_1.pdb
            │   │   ├── sc_results.csv # Self consistency summary metrics CSV
            │   │   └── seqs
            │           └── sample_1.fa # ProteinMPNN sequences
            └── sample_1

Note that saved models can be found here for base, optimal transport (OT) and stochastic (SFM) foldflow models.

Training

Getting Started: Training FoldFlow on one protein

To get started and to make sure the code is working we recommend starting by training foldflow-base on a single protein. This should immediately work and produce the protein 2f60 in PDB.

python runner/train.py local=example

We expect this to converge in ~1500 steps and ~10-20 minutes on a V100. To train an OT model run:

python runner/train.py local=example flow_matcher.ot_plan=True

to train foldflow-sfm run:

python runner/train.py local=example flow_matcher.ot_plan=True flow_matcher.stochastic_paths=True

Training on the Full Dataset

To get the full dataset, we supply two options:

  1. We supply the full dataset in preprocessed form [here] TODO WHERE.
  2. It can either be reprocessed from PDB using the steps described in the se3_diffusion repository. We find (1) easier, but may become out of date as more PDBs are released.
1. Downloading and unpacking our preprocessed data.

We supply our metadata.csv file, which can be used to reproduce an identical training set in data/metadata.csv. Note that this file assumes all pickled data is located in data/processed_pdbs/, a new location requires rewriting this csv file.

We also supply our saved data as tar file [here] TODO WHERE. Which can be extracted with

tar xvzf processed_pdbs.tar.gz

This may take a few minutes and requires ~32GB of disk space while unpacking.

2. Downloading from PDB for training.

To get the training dataset, first download PDB then preprocess it with the provided scripts. PDB can be downloaded from RCSB: https://www.wwpdb.org/ftp/pdb-ftp-sites#rcsbpdb. Our scripts assume you download in mmCIF format. Navigate down to "Download Protocols" and follow the instructions depending on your location.

WARNING: Downloading PDB can take up to 1TB of space.

After downloading, you should have a directory formatted like this: https://files.rcsb.org/pub/pdb/data/structures/divided/mmCIF/

00/
01/
02/
..
zz/

In this directory, unzip all the files:

gzip -d **/*.gz

Then run the following with <path_pdb_dir> replaced with the location of PDB.

python process_pdb_dataset.py --mmcif_dir <pdb_dir>

See the script for more options. Each mmCIF will be written as a pickle file that we read and process in the data loading pipeline. A metadata.csv will be saved that contains the pickle path of each example as well as additional information about each example for faster filtering.

Download the clusters at 30% sequence identity at rcsb. This download link also works at time of writing:

https://cdn.rcsb.org/resources/sequence/clusters/clusters-by-entity-30.txt

Place this file in data/processed_pdb or anywhere in your file system. Update your config to point to the clustered data:

data:
  cluster_path: ./data/processed_pdb/clusters-by-entity-30.txt

You can add the paths of to your data directly in runner/config/data/default.yaml or by adding your local configuration in runner/config/local. We suggest the latter, as it makes it easier to share your code with others. We provide an example of such configuration in runner/config/local/example.yaml.

Evaluating Protein Models

Eval code coming soon!

Toy SO(3) examples

Please find all the jupyter notebooks in so3_experiments, they are designed to be minimalistic and easy to follow and may be useful for other projects for applications of Flow Matching on SO(3).

To run our jupyter notebooks, use the following commands after installing our package.

# install ipykernel
conda install -c anaconda ipykernel

# install conda env in jupyter notebook
python -m ipykernel install --user --name=foldflow

# launch our notebooks with the foldflow kernel

Third party source code

Our repo keeps a fork of OpenFold and ProteinMPNN. Each of these codebases are actively under development and you may want to refork. Several files in /data/ are adapted from AlphaFold.

Citation

If this codebase is useful towards other research efforts please consider citing us.

@inproceedings{bose2024se3stochastic,
      title={SE(3)-Stochastic Flow Matching for Protein Backbone Generation},
      author={Avishek Joey Bose and Tara Akhound-Sadegh and Guillaume Huguet and Killian Fatras and Jarrid Rector-Brooks and Cheng-Hao Liu and Andrei Cristian Nica and Maksym Korablyov and Michael Bronstein and Alexander Tong},
      year={2024},
      booktitle={The International Conference on Learning Representations (ICLR)},
}

Contribute

We welcome issues and pull requests (especially bug fixes) and contributions. We will try our best to improve readability and answer questions!

Licences

FoldFlow by Dreamfold is licensed under Attribution-NonCommercial 4.0 International