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

Virtual Reality: A Railroad for Structural Bioinformatics towards Advanced Cancer Research

ABSTRACT 11 Technology has been a part of everyone's life for decades now, and its impact on our lifestyle only 12 seems to increase with time. Considering applications in the field of scientific research till date, it 13 has made exponential advancements and created a new hallmark. 'Virtual Reality' is one of the 14 most applicable, impressive and recently uplifted technologies that has been implemented in 15 numerous approaches already. In the light of structural biological studies, virtual reality technology 16 enables immersive 3D visualization of molecular structures, interactions, mechanisms etc., and 17 molecular modelling at the atomic level facilitating a better understanding of the 'science behind 18 the scene'. In molecular cancer studies, this helps peruse and diagnose defective root causes and 19 unveil effective therapeutic approaches. Although this technology has primarily interested a huge 20 number of researchers and institutes performing structural bioinformatics studies, many researchers 21 across the globe and a large section of the public are still in the dark about its practicality and 22 benefits, some of the main reasons being lack of exposure and the issue with affordability. Thus, 23 besides shedding light on the various ways in which virtual reality has been lately implied to cancer 24 research and therapy, this article aims to promote and encourage usage of a simple, cost-effective 25 platform for 3D immersive visualization of molecular structures for the insufficiently funded 26 community to begin with experiencing molecular virtual reality. It also intends to propose a new 27 permutation of concepts to contribute to an advanced approach in structural cancer studies where 28 scientists can superlatively immerse into the cellular environments and seek answers by virtually 29 communicating with the entities in the microscopic realm. This versatile technology has thus far 30 inevitably proven to possess an enormous potential and is already underway in revolutionizing 31 education, training, scientific research and medical therapy. This article aims to educate more 32 people about prevailing VR technologies and primarily to help accelerate this futuristic technique 33 in cancer research and therapeutics. Albeit leading to a progress in scientific exploration, it could 34 also spread hope and soon assist in upgrading the quality of living especially for cancer victims. 35 3

Data associated with 'Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region'

The T cell receptor (TCR-CD3) initiates T cell activation by binding to peptides of Major Histocompatibility Complexes (pMHC). The TCR-CD3 topology is well understood but the arrangement and dynamics of its cytoplasmic tails remains unknown, limiting our grasp of the signalling mechanism. Here, we use molecular dynamics simulations and modelling to investigate the entire TCR-CD3 embedded in a model membrane. Our study demonstrates conformational changes in the extracellular and transmembrane domains, and the arrangement of the TCR-CD3 cytoplasmic tails. The cytoplasmic tails formed highly interlaced structures while some tyrosines within the immunoreceptor tyrosine-based activation motifs (ITAMs) penetrated the hydrophobic core of the membrane. Interactions between the cytoplasmic tails and phosphatidylinositol phosphates lipids in the inner membrane leaflet led to the formation of a distinct anionic lipid fingerprint around the TCR-CD3. These results increase our understanding of the TCR-CD3 dynamics and the importance of membrane lipids in regulating T cell activation

Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region.

The T cell receptor (TCR-CD3) initiates T cell activation by binding to peptides of Major Histocompatibility Complexes (pMHC). The TCR-CD3 topology is well understood but the arrangement and dynamics of its cytoplasmic tails remains unknown, limiting our grasp of the signalling mechanism. Here, we use molecular dynamics simulations and modelling to investigate the entire TCR-CD3 embedded in a model membrane. Our study demonstrates conformational changes in the extracellular and transmembrane domains, and the arrangement of the TCR-CD3 cytoplasmic tails. The cytoplasmic tails formed highly interlaced structures while some tyrosines within the immunoreceptor tyrosine-based activation motifs (ITAMs) penetrated the hydrophobic core of the membrane. Interactions between the cytoplasmic tails and phosphatidylinositol phosphate lipids in the inner membrane leaflet led to the formation of a distinct anionic lipid fingerprint around the TCR-CD3. These results increase our understanding of the TCR-CD3 dynamics and the importance of membrane lipids in regulating T cell activation