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

Area of Science:

• Immunology
• Biophysics
• Computational Biology

Background:

• Mechanical forces on T-cell receptors (TCRs) are critical for recognizing peptide-MHC complexes.
• Previous simulations identified TCR inter-domain motion as key to load-induced catch bonds and peptide discrimination.

Purpose of the Study:

• To investigate the generality of the TCR-pMHC mechanical load mechanism.
• To compare the B7 TCR-pMHC interaction with previous findings on the A6 TCR.

Main Methods:

• All-atom molecular dynamics (MD) simulations were performed on the B7 TCR under varying conditions.
• Simulations compared the B7 TCR's behavior to the previously studied A6 TCR, which recognizes the same pMHC.

Main Results:

• The B7 TCR-pMHC interface stabilizes under ~15 pN load via dynamic allostery and asymmetric TCR chassis motion.
• Despite similar crystal structure contacts to A6 TCR, B7 TCR showed fewer high-occupancy contacts and greater mechanical compliance.
• A conserved dynamic allostery mechanism within the TCRαβ chassis was identified.

Conclusions:

• Dynamic allostery in TCRs can translate subtle differences in interfacial contacts into distinct mechanical responses.
• This mechanism contributes to nuanced biological outcomes in T-cell activation and recognition.