The Influences of Conformational Dynamics on T Cell Receptor Specificity and Cross-reactivity

Multi-specificity is a hallmark of T cell receptor (TCR) recognition, as a high volume of antigen must be identified by the T cell arm of the immune system. The mechanism by which a TCR engages a potential ligand and distinguishes its composition as either foreign or self – and doing this many times over with a diverse array of ligands – is a remarkable operation that remains mechanistically ambiguous. Protein-protein interactions have been characterized by a wide variety of biophysical and structural methods, which have resolved many key attributes of the interaction process. This is certainly the case of the TCRs and their antigen, peptides bound to cell-associated major histocompatibility complex (pMHC). However, holes in the arguments for how the recognition process is carried out are extremely confounding, calling for new approaches to more fully characterize the mechanism of TCR-pMHC recognition.

It has been well-established that protein function is heavily influenced by the dynamic properties of a protein. Conformational diversity of TCRs has been revealed through crystallographic and thermodynamic data, yet the pre-existing flexibility of the receptor at its binding surface has gone relatively unidentified. Here we address the fundamental dynamics of the A6 TCR protein, and consider the potential effects its conformational variability may impose on its recognition strategy. By the means of time-resolved fluorescence anisotropy and molecular dynamics simulations, distinct and measureable flexibilities of the antigen-binding loops of A6 have been determined. Towards the ultimate goal of elucidating the receptor's recognition mechanism, a comprehensive analysis of the data from both structural and energetic perspectives have been critically performed.