Molecular Dynamics Simulations and Modelling of the T cell receptor and the Lymphocyte-specific Protein Tyrosine Kinase

The T cell antigen receptor (TCR-CD3) is an octameric protein complex located in the T cell plasma membrane. It plays a vital role in our adaptive immune system by recognising a wide variety of antigenic peptides attached to major histocompatibility complexes (pMHCs). Upon binding with pMHCs, the TCR-CD3 transmits a signal to its unstructured cytoplasmic region which undergoes phosphorylation by the lymphocyte-specific protein tyrosine kinase (LCK), further triggering a chain of events ultimately aiding in T cell-mediated immune response. Despite studies conducted on the structure and function of the TCR-CD3 and LCK, we do not yet understand the initial phase of T cell activation in molecular detail. To achieve this, it is important to not only know their structure but also study their dynamic behaviour in their native environment on the nanosecond to microsecond time-scales. Given the lack of structural data on the TCR-CD3 cytoplasmic region and the full-length LCK, molecular modelling employed in this thesis has helped produce their complete models and enabled molecular dynamics simulation studies. Supported by prior experimental evidence, the simulations conducted in this thesis have led to novel findings such as: (i) specific sites in the TCR-CD3 transmembrane region that potentially help transmit pMHC-induced signals into the cytoplasmic region, (ii) TCR-CD3 dynamics in a membrane and the arrangement of its cytoplasmic region, (iii) PIP lipid interactions and clustering around the TCR-CD3 and upon the association of LCK with the membrane, (iv) TCR-CD3 conformational changes, and (v) protein-protein/lipid interactions in the open and closed LCK conformations. Overall, this thesis provides novel molecular-level insights into the dynamics of the TCR-CD3 and LCK, and also signifies the potential of molecular dynamics simulations in studying membrane-associated proteins. Further, this work encourages computational studies of other immunoreceptors to help understand various immune mechanisms and aid in clinical therapeutics.