Inherent plasticity of a T-cell receptor binding interface prior to pMHC recognition (78.2)

Abstract

Abstract Structural and biophysical studies have established that the recognition of antigenic peptide-MHC complexes (pMHC) by T-cell receptors (TCR) involves conformational changes in the so-called CDR loops, which define the binding interface of the TCR. This plasticity is believed to underlie the receptors' cross-reactivity, a key feature given the vast diversity of antigens and the limited T-cell repertoire. It remains unclear, however, whether this plasticity is induced upon recognition of specific pMHC, or whether it is an intrinsic characteristic of the CDR loops. To gain insights into this question, we present results from large-scale, atomically-detailed computer simulations of the molecular dynamics of a TCR in its unliganded form and in complex with two distinct pMHC. Our results indicate that the CDR loops can populate bound-like conformational states prior to the engagement of the pMHC, and thus, that the structural plasticity of the binding interface is indeed inherent. It follows that cross-reactivity of this TCR may not be solely determined by their potential interactions with specific pMHC complexes, but also by the nature of this pre-existing conformational equilibrium.