Secondary Structure-Guided Novel Protein Sequence Generation with Latent Graph Diffusion

🚀 Introduction (CPDiffusion-SS)

CPDiffusion-SS is composed of three primary components: a sequence encoder, a latent diffusion generator, and an autoregressive decoder.

The sequence encoder embeds AA sequences into a latent space of secondary structure-level (SS-level) representations, while the decoder maps the generated SS-level latent representation back to the AA space. The central module is a latent graph diffusion model that generates diverse SS-level hidden representations within the established latent space.

📑 Results

News

• [2024.06.29] our paper was presented ICMLw 2024
• [2024.10.14] our paper was accepted as a regular paper at BIBM 2024

Paper Results

we compare CPDiffusion-SS with both sequence and structure-based baseline methods on 10 evaluation metrics concerning the diversity, novelty, and consistency of the generated sequences. CPDiffusion-SS outperforms all baselines in consistency while maintaining high diversity and novelty.

Case Study

Predicted 3D structures and composition of secondary structures on three cases from the test dataset. Here we use red, yellow, and blue colors to represent helices (H), sheets (E), and coils (C), respectively.

🛫 Requirement

Conda Enviroment

Please make sure you have installed Anaconda3 or Miniconda3.

step1: download ESM2

1. Manually download the ESM2 model from https://huggingface.co/facebook/esm2_t33_650M_UR50D.
2. Save the downloaded model file to the directory CPDiffusion-SS/models/esm2_t33_650_UR50D/.

step2: install package

1. install dssp-2.2.1

conda install -c ostrokach dssp

2. install biopython, torch_geometric

pip install biopython
pip install torch_geometric==2.4.0

3. install other packages required

🧬 Start with CPDiffusion-SS

Data Process

1. Prepare your dataset

you will need a dataset in pdb format

2. split dataset

split the dataset and put the pdb files to "data/data_split_name/pdb"

3. data process

python dataset_pipeline.py --dataset CATH43_S40_SPLIT_TRAIN_VAL

Train

Step1: Train Encoder-Decoder

python train_encoder_decoder.py --batch_size 10 --wandb --dataset AFDB --val_num 360000 --encoder_type AttentionPooling --patience 4 --wandb_run_name decoder_ESM2_AFDB_AttentionPooling_train  --model_name decoder_ESM2_AFDB_AttentionPooling.pt

args:

1. --decoder_ckpt (Optional): Train from Encoder-Decoder checkpoint.
2. --model_name: Encoder-Decoder checkpoint will be saved as results/decoder/ckpt/date/model_name

Step2: Train Diffusion

python train_diff.py --wandb --wandb_run_name diffusion_CATH43S40_SPLIT --dataset CATH43_S40_SPLIT_TRAIN_VAL --decoder_ckpt './results/decoder/ckpt/20240227/decoder_ESM2_AFDB_AttentionPooling.pt' --diff_batch_size 100

args:

1. --wandb (Optional): delete this parameter to turn off wandb(https://wandb.ai/)
2. --wandb_run_name: run name in wandb & diffusion model saved as results/diffusion/weight/date/wandb_run_name.pt
3. --decoder_ckpt: check point of Encoder-Decoder

🔬 Benchmark

Metrics

Metric Name	type	Detailed information
TM_new	Diversity	average pairwise TM-scores of all generated sequences
RMSD	Diversity	average pairwise RMSD of all generated sequences
Seq. ID	Diversity	average pairwise sequence identities of all generated sequences
TM_wt	Novelty	average TM-score between the generated protein and the most similar protein in training set
ID	Consistency	average identities in secondary structure sequences between top10 generated proteins and the target
ID_max	Consistency	highest identities in secondary structure sequences between generated proteins and the target
MSE	Consistency	average MSE in secondary structure compositions between generated proteins and the target

Experiments

Environment Setup

 conda install -c conda-forge -c bioconda mmseqs2 -y
 conda install -c conda-forge -c bioconda foldseek -y
 conda install -c schrodinger tmalign -y
 conda install -c conda-forge pymol-open-source -y

Weights Download

Download checkpoints from huggingface repository

huggingface-cli download --resume-download riacd/CPDiffusion-SS

Move decoder model weights to directory "results/decoder/ckpt/"

Move diffusion model weights to directory "results/diffusion/weight/"

Run

python metrics.py

🙌 Citation

Please cite our work if you have used our code or data.

@inproceedings{hu2024secondary,
  title={Secondary structure-guided novel protein sequence generation with latent graph diffusion},
  author={Hu, Yutong and Tan, Yang and Han, Andi and Zheng, Lirong and Hong, Liang and Zhou, Bingxin},
  booktitle={2024 IEEE International Conference on Bioinformatics and Biomedicine (BIBM)},
  pages={31--41},
  year={2024},
  organization={IEEE}
}