PT  - JOURNAL ARTICLE
AU  - Joseph S. Murray
TI  - Somatic genetics of CDR3 control H-bonds to MHC via V-domain rotational probability (<em>d</em>V) effecting germline CDR2 ‘scanning’ (<em>d</em>θ) of polymorphic MHC
AID  - 10.1101/796052
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 796052
4099  - http://biorxiv.org/content/early/2019/10/07/796052.short
4100  - http://biorxiv.org/content/early/2019/10/07/796052.full
AB  - The mechanism which ‘adapts’ the T-cell antigen receptor (TCR) repertoire within a given major histocompatibility complex (MHC; HLA, in humans) genotype is essential for protection against rapidly dividing pathogens. Historically attributed to relative affinity, genetically vast TCRs are surprisingly “focused” towards a micromolar affinity for their respective pHLA 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 equation (from fixed geometry) for any given V-domain in TCR bound to pMHC. We examined solved complexes involving HLA-DR and HLA-DQ, where all the available structures are still reasonably analysed. Certain V-beta domains displayed “rare” geometry within this panel—specifying a very low (“highly-restricted”) rotational probability/volumetric density (dV). Remarkably, hydrogen (H)-bond charge-relays spanning CDR3-beta, the peptide, and polymorphic MHC distinguished these structures from the others; suggesting that CDR3 binding chemistry dictates CDR2 ‘scanning’ on the respective MHC-II alpha-helix. Taken together, this analysis (n = 38 V-domains) supports a novel geometric theory for MHC restriction—one not constrained by a thymus “optimized” TCR-affinity.