CDR3 binding chemistry controls TCR V-domain rotational probability and germline CDR2 scanning of polymorphic MHC

•By spherical coordinates (multivariable calculus), a TCR V-domain volume element was clonotypic within a panel of TCR: pMHC class-II complex structures.•Rare V-domains displayed “highly restricted” dV (rotational probability).•H-bonding networks of CDR3 binding to highly conserved MHC alpha-helix motifs correlated with the highly restricted V-domains.•CDR2 “scanning” (dθ) of a polymorphic MHC-II alpha helical region correlated with dV by an across-the-groove rotation of 45 degrees.•Transition-state theory and stereochemically governed binding thermodynamics are consistent with a V-domain rotational dynamics mechanism controlling aspects of T-cell biology previously attributed to relative binding affinity of the α/β TCR engagement with pMHC-II. The mechanism which adapts the T-cell antigen receptor (TCR) within a given major histocompatibility complex (MHC/HLA) genotype is essential for protection against pathogens. Historically attributed to relative affinity, genetically vast TCRs are surprisingly focused towards a micromolar affinity for their respective peptide (p) plus MHC (pMHC) ligands. Thus, the somatic diversity of the TCR with respect to MHC-restriction, and (ultimately) to pathogens, remains enigmatic. Here, we derive a triple integral solution (from fixed geometry) for any given V domain in TCR bound to pMHC. Solved complexes involving HLA-DR and HLA-DQ, where genetic linkage to the TCR is most profound, were examined in detail. Certain V domains displayed rare geometry within this panel—specifying a restricted rotational probability/volumetric density (dV). Remarkably, hydrogen (H) bond charge-relays distinguished these structures from the others; suggesting that CDR3 binding chemistry dictates CDR2 contacts on the opposite MHC-II alpha helix. Together, these data suggest that TCR recapitulate dV and specialise target pMHC recognition. As such, there are implications for the design of TCR-based therapeutics.