ESMIFDesign

This repository focuses on designing T-cell receptors (TCRs) using the ESM-IF1 deep learning method.

The ESM-IF1 inverse folding method is built for predicting protein sequences from their backbone atom coordinates. Here, we use the ESM-IF1 model (esm_if1_gvp4_t16_142M_UR50 - fair-esm v2.0.1) to design part of the TCRs sequences, considering their peptide-major histocompatibility complex (pMHC) complex. Positions outside the specified criteria were held constant. The designed positions were changed to <mask> tokens, and all amino acid substitutions, including cysteine, were allowed. Given the multi-chain structure, a padding of 10 <pad> tokens was used to separate the chains.

Dependencies

To install the dependencies, run:

pip install -r requirements.txt

Usage

The configuration file is located at config.json, where it specifies, for each structure, the residues and chains to be designed. The file is organized as follows:

{
    "6zkw": ["110D","111D","112D","134D","135D","113E","114E","133E"],
    ...,
    "8shi": ["109D","110D","111D","112D","113D","114D","135D","110E","111E","112E","113E","134E","135E"]
}

To design TCR sequences, run:

python run.py

Testing

We tested some conditions to check the performance of the model.

1. Testing on 6ZKW structure:
   • 6ZKW.pdb represents a TCR-pMHC complex.
   • 6ZKW_DE.pdb includes only the TCR (D and E chains).
   • 6ZKW_contact_to_gly.pdb is a TCR-pMHC complex with mutations on the TCR residues in contact with the pMHC, changing them to glycine.
   • 6ZKW_all_gly.pdb is a TCR-pMHC complex with mutations on all residues, changing them to glycine.
2. Testing on pMHC interference on protein sequence design (tests/pMHC1.config)
3. Testing temperature in the interval (tests/temperature.config): [1e-6, 1e-5, 1e-4, 1e-3, 1e-2, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 2, 5]
4. Testing number of samples in the interval (tests/sampling.config): [5, 10, 25, 50, 100, 250, 500]
5. Testing design approaches:
   • CDR3 interface (tests/CDR3_interface.config): restricting the design to CDR3 (α and β TCR chains) within a proximity of 5 Å to either the peptide or MHC;
   • CDR3 (tests/CDR3.config): designing the entire CDR3 (α and β TCR chains).
   • CDRs interface (tests/CDRs_interface.config): designing CDR1, CDR2, or CDR3 positions (α and β TCR chains) within a 5 Å distance to the peptide or MHC;

To run the tests, navigate to the tests directory and execute:

cd tests
python testing.py