Atomic Coordination Reflects Peptide Immunogenicity

Area of Science:

• Immunology
• Computational Chemistry
• Structural Biology

Background:

• Accurate prediction of peptide-MHC-TCR interactions is crucial for understanding immune responses.
• Existing methods may not fully capture the subtle structural determinants of T cell recognition.

Purpose of the Study:

• To develop a predictive metric for the immunological identity of peptide variants based on structural properties.
• To identify structural features associated with T cell activation by peptide agonists.

Main Methods:

• Analysis of atomic coordination differences between variant and native peptide structures (both unprotonated and protonated).
• Computational modeling of molecular orbital interactions and peptide N-terminus stability.
• Quantum chemical calculations for protonated structures under various conditions.

Main Results:

• Atomic coordination difference accurately predicts peptide immunological identity, with increasing difference correlating to weaker immune outcomes.
• The predictive metric is effective at the peptide scale but diminishes beyond 7 Å.
• Agonistic peptides consistently exhibit a stable ammonium group at the N-terminus, absent in antagonists, indicating T cell activation.

Conclusions:

• Coordination difference serves as a reliable metric for predicting peptide immunological identity.
• The N-terminal ammonium group is a key structural marker for T cell activation by peptide agonists.
• These findings offer insights into the structural basis of T cell recognition and immune response modulation.