Molecular Dynamics Simulation Study On Self-assembly Of Transmembrane Domain Of TCR-CD3 Complex

The T cell receptor-CD3(TCR-CD3)complex plays an important role in the adaptive immune response,and the interaction between its subunits has always been a hot research topic.With the analysis of the electron microscope structure of the TCR-CD3 complex,the relative position between the complexes has become clear,but the detailed molecular mechanism of the assembly has not been completely clear,and the transmembrane protein is difficult to separate.Traditional experimental techniques have The research is also very limited.Therefore,we combined the three simulation methods of coarse-grained simulation,all-atom simulation,and stretch dynamics simulation to analyze the self-assembly molecular mechanism of the TCR-CD3 complex transmembrane domain,as well as the binding force between its subunits.Limited by the simulation system and the simulation time scale,we used coarse-grained simulation to analyze the self-assembly of the TCR-CD3 complex in the transmembrane domain.The results indicate that the transmembrane domain of the TCR-CD3 complex alone is not sufficient to mediate the specific interaction between its subunits.At the same time,through the mutation of key residues,it is explained that the mutation of αR253 can reduce the interaction between αK258 and δε’-DD.It is also proved from the perspective of molecular dynamics simulation that there is an assembly sequence of αβ combining with δε’,γε,and ζζ’ in sequence in the assembly process of TCR-CD3 complex.The δε’,γε,and ζζ’ were pulled apart to completely separate from the rest of the complex through the steered dynamics simulation,and the required force was compared to analyze the binding characteristics of the extracellular domain and the transmembrane domain.It is concluded that the extracellular domain of ζζ’ is more important than the transmembrane domain in the assembly process,which is different from other dimers.The all-atom simulation analysis of the effect of the loss of each dimer on other dimers shows that the loss of 8s’ has the greatest impact on the stability of the rest of the TCR-CD3 complex,and the loss of ζζ’ hardly affects the stability of the remaining parts.Using molecular dynamics simulation methods to study the molecular mechanism of TCR-CD3 complex self-assembly is of great significance for the development of T cell receptor immunotherapy.