Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity

Area of Science:

• Immunology
• Structural Biology
• Computational Biology

Background:

• T cell receptor (TCR) recognition of antigens is crucial for adaptive immunity.
• TCR specificity is often difficult to predict from static protein structures.
• Antigen cross-reactivity is an inherent property of TCRs, necessitating high specificity.

Purpose of the Study:

• To elucidate the molecular mechanism underlying TCR specificity for a neoantigen presented by HLA-A3.
• To investigate how dynamic motions in the peptide-binding groove influence TCR-pMHC interactions.
• To understand the structural basis for discriminating between a neoantigen and its wild-type counterpart.

Main Methods:

• Molecular dynamics simulations of HLA-A3 presenting wild-type and neoantigen peptides.
• Analysis of conformational changes in the HLA-A3 peptide binding groove.
• TCR binding assays to assess specificity.

Main Results:

• Distinct dynamic motions were observed in the HLA-A3 peptide binding groove depending on the peptide's anchor residue.
• These motions form a dynamic gate that restricts TCR binding to the wild-type peptide.
• The neoantigen bypasses this gate, enabling TCR engagement and a unique conformational change involving tryptophan translocation.

Conclusions:

• TCR specificity is driven by dynamic and allosteric mechanisms within the peptide/MHC-I binding groove.
• Peptide-induced conformational changes in MHC molecules are critical for TCR discrimination.
• This provides a novel framework for understanding T cell recognition of cancer neoantigens.