T-cell receptors binding orientation over peptide/MHC class I is driven by long-range interactions

Area of Science:

• Structural biology
• Computational biophysics
• Immunology

Background:

• T-Cell Receptor (TCR) and peptide-MHC (pMHC) interactions are crucial for adaptive immunity.
• Diverse TCR binding modes complicate antigen recognition and understanding TCR orientation over pMHC remains a challenge.

Purpose of the Study:

• To develop a simplified rigid model to predict TCR orientation on pMHC.
• To investigate the role of long-range electrostatic interactions in TCR-pMHC complex formation.
• To identify key residues and regions driving TCR-pMHC binding.

Main Methods:

• Applied a rigid approach to non-redundant TCR-pMHC crystal structures.
• Utilized CHARMM force field and FACTS implicit solvation model.
• Analyzed Coulomb and electrostatic solvation energies, and decomposed electrostatic energy by residue.

Main Results:

• The model identified two stable orientations (0° and 180°) based on electrostatic interactions, robust to minor structural changes.
• Shape complementarity is not essential for accurate orientation prediction.
• CDR1,2/MHC interactions were found to be the primary drivers of complex formation, independent of short-range forces or induced fit.
• The approach successfully predicted binding modes for homology-modeled TCR structures.

Conclusions:

• A simplified electrostatic model can accurately predict TCR-pMHC binding orientations.
• Long-range CDR1,2/MHC interactions are critical and precede specific binding.
• This method offers a computationally efficient and broadly applicable tool for studying macromolecular interactions.