T-Cell Receptor CDR3 Loop Conformations in Solution Shift the Relative Vα-Vβ Domain Distributions

Area of Science:

• Immunology
• Structural Biology
• Computational Biology

Background:

• T-cell receptors (TCRs) are crucial for adaptive immunity, recognizing foreign peptides presented by MHC molecules.
• Complementarity Determining Regions (CDRs), especially CDR3 loops, dictate peptide recognition and TCR binding affinity.
• Current understanding often relies on limited canonical structures for CDR3 loops.

Purpose of the Study:

• To kinetically classify T-cell receptor CDR3 loops based on their solution structures.
• To explore the conformational diversity of CDR3 loops beyond static X-ray structures.
• To investigate the relationship between CDR3 loop conformations and TCR-MHC interactions.

Main Methods:

• Molecular dynamics simulations were employed to sample CDR3 loop conformations.
• Kinetic analysis was used to classify canonical and non-canonical structures.
• Correlations between CDR3 loop states and Vα-Vβ interdomain orientations were identified.

Main Results:

• A broader ensemble of CDR3 loop conformations was observed in solution, including distinct kinetic minima.
• Multiple canonical structures are necessary to fully describe the conformational diversity of CDR3 loops.
• Conformational selection, rather than antigen-induced fitting, governs binding-competent states.
• CDR3 loop conformations are strongly dependent on Vα-Vβ interdomain orientations.

Conclusions:

• TCR CDR3 loops should be characterized as dynamic conformational ensembles in solution.
• The identified solution structures expand the repertoire of known canonical clusters.
• Understanding these ensembles is vital for characterizing peptide recognition and TCR function.