Load-based divergence in the dynamic allostery of two TCRs recognizing the same pMHC

Area of Science:

• Immunology
• Biophysics
• Computational Biology

Background:

• Mechanical load on the alpha-beta T cell receptor (TCR) is increasingly recognized as vital for distinguishing peptide-MHC complexes.
• Previous all-atom molecular dynamics (MD) simulations identified TCR inter-domain motion as responsible for load-induced catch bond behavior and peptide discrimination.

Purpose of the Study:

• To investigate the generality of the load-induced TCR-pMHC interaction mechanism.
• To compare the mechanical behavior of the B7 TCR with the previously studied A6 TCR using all-atom MD simulations.

Main Methods:

• All-atom molecular dynamics (MD) simulations were performed on the B7 TCR-pMHC complex under varying conditions.
• Simulations were compared to previous MD data for the A6 TCR-pMHC complex, which recognizes the same peptide-MHC.

Main Results:

• The B7 TCR-pMHC interface demonstrated stabilization under a ~15-pN load, mediated by a conserved dynamic allostery mechanism involving asymmetric TCR chassis motion.
• Despite similar crystal structure contacts with pMHC compared to A6, the B7 TCR exhibited fewer high-occupancy contacts and greater mechanical compliance.
• The conserved dynamic allostery in the TCR alpha-beta chassis can significantly amplify subtle differences in interfacial contacts.

Conclusions:

• Dynamic allostery is a conserved mechanism within the TCR alpha-beta chassis that influences mechanical responses.
• Minor variations in TCR-pMHC interfacial contacts can lead to distinct mechanical behaviors and biological outcomes.
• This study highlights how conserved allosteric mechanisms contribute to nuanced immune recognition.