Computational Analysis of TCR Load Propagation and Dynamics

Dana-Farber Cancer Inst, Boston MA

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Abstract

Summary (Project 3) Recent discoveries indicate the αβT-cell receptor (TCR) is a mechanosensor in recognizing the antigenic peptide-loaded major histocompatibility complex (pMHC) molecule. For the cognate antigen, the TCR-pMHC bond lifetime increases with force, reaching a maximum at forces comparable to those generated between a T cell and an antigen-presenting cell during immune surveillance. Once the catch bond forms, the TCR-pMHC complex may enter cycles of conformational transitions between compact and extended states termed volleying. Our past molecular dynamics simulations of the complex under force revealed that ligand recognition and catch bond formation is mediated not only by the contacts at the TCR-pMHC interface, but that the conformational dynamics of the whole complex plays a critical role. We shall further advance our computational efforts to address emerging questions regarding the TCR mechanosensing. In Aim 1, by developing methods to measure strains and stresses across the dynamically fluctuating TCR-pMHC complex, we will find the load propagation pathway, which we hypothesize to be a determining factor for the memory T cell lineage. In Aim 2, using a novel simulation protocol, we will also find the loading condition under which partial unfolding of the TCR constant domain occurs, to enter the volleying state. The ability for an αβTCR to form catch bond and volley is important for recognizing ligands displayed in low copy numbers on antigen-presenting cell. As a first step to understanding how the conformational dynamics of the TCR-pMHC complex initiates signaling for T-cell activation, in Aim 3 we will simulate the organization of the transmembrane domains of the αβTCR holoreceptor including the CD3 signaling subunits. Based on this, effects of the ectodomain conformational dynamics upon pMHC ligation on the transmembrane domain assemblies will be investigated. Our overarching strategy consists of performing all-atom simulations on parts of the system to obtain detailed atomistic information, then perform simulations of larger assemblies using implicit solvent, coarse-grained, and kinetic models for computational efficiency and to directly compare with experiments. These approaches will also be used to investigate the preTCR-pMHC complex as a mechanosensor, where high-affinity mutant preTCR or peptide will be designed to study β-selection in T-lineage progenitor differentiation experiments. To be developed in close collaboration with experimental partners within our team, atomistic mechanisms of TCRs and preTCRs found via simulations will help with developing T-cell immunotherapy protocols where mechanical force and ligand density are crucial.