Dichotomy in TCR V-domain dynamics binding the opposed inclined planes of pMHC-II and pMHC-I α-helices

Abstract

Ligand recognition by the human α/β T-cell antigen receptor (TCR) heterodimer protein, unlike the surface immunoglobulin (sIg) B-cell receptor, is not governed by relative binding affinity. Its interaction with the peptide (p) plus major histocompatibility complex (MHC) protein (abbrev. pMHC) involves some different molecular mechanism linking pMHC binding to T-cell functions. Recent analytical geometry of TCR:pMHC-II solved crystallographic structures (n = 40) revealed that each variable (V)-domain is bound in similar, yet mathematically unique orientations to its target pMHC groove. The relative position of the central cysteine of each V-domain was examined by multivariable calculus in spherical coordinates, where a simple volume element (dV) was found to describe clonotypic geometry with pMHC-II. Here, the study was expanded to include TCR:pMHC-I structures, and to model a physical mechanism, specifically involving the two directionally opposed inclined planes (IP) manifest by the two major α-helices prominent in both MHC-I and MHC-II proteins. Calculations for rotational torque of each V-domain, together with acceleration up and down the slopes of both MHC α-helices, were used to estimate the time a given V-domain spends sliding down its cognate MHC IP. This V-domain rotation/sliding mechanism appears to be quantitatively unique for each target TCR:pMHC complex. However, there is a common dichotomy between the mobility of each V-domain with respect to the two classes of MHC proteins. In both TCR:pMHC-I and TCR:pMHC-II, one V-domain positions consistently between different structures, while the other V-domain shows position variability. Strikingly, which of the V-domains is consistent or variable are opposites between the two MHC classes. The implications for TCR selection in the thymus, and peripheral T-cell activation utilizing this quaternary dynamics information could have directed evolution of extant T-cell biology.