Dottorato in SCIENZE CHIMICHE

Titolo della tesi: The effect of the conformational behaviour of TCR related proteins on their function: a computational approach

T lymphocytes play an essential role in the adaptive immuno-response, thus they represent an efficient system of defense against foreign pathogens, and an effective mechanism in cancer surveillance. However, T cells are also involved in some autoimmune diseases such as diabetes mellitus type I, multiple sclerosis and Crohn’s disease. The activation of the T cell is regulated by the TCR, a transmembrane receptor, which interacts - in the extracellular region - with the pMHC (a protein expressed on almost all the cells) to recognize self and non-self peptides. The TCR is non-covalent bound to its co-receptor, CD3, which interacts in the transmembrane region. Following the TCR triggering, the tyrosines located on specific a.a. sequences of CD3, called ITAMs, are phosphorylated by a Src kinase protein, such as Lck. Many questions about how the T cell activation occurs are still unanswered, in particular: i) it is unclear how the TCR can discriminate between self and non-self peptide; ii) it was supposed that the TCR triggering induces conformational changes affecting the CD3 chains, improving their exposure to Lck. However, such an event is still undemonstrated. To give our contribution in answering these questions, in this Thesis, a structural and dynamical characterization of the TCR related proteins – as c-Src, Lck, pMHC, TCR and CD3 - was provided, by means of computational approaches. We were able to describe the activation/inactivation pathways in Src kinase proteins, also in presence of an inhibitor, using Molecular Dynamics simulations and an enhanced sampling technique, called the Essential Dynamic sampling. Moreover, a study of the conformational behavior of several pMHC:TCR interactions was provided in a lipid environment. Finally, the first computational description of the conformational behavior of the full complex pMHC:TCR:CD3-chains was produced to identify any conformational changes caused by the TCR triggering.