The T-cell receptor (TCR) interaction with antigenic peptides (p) presented by the major histocompatibility complex (MHC) molecule is a key determinant of immune response. Although their importance, molecular details determining TCR-pMHC binding remain unsolved. In particular, how the peptide can be recognized by the TCR, and what is the TCR contribution in this recognition, are questions still unanswered. Molecular dynamics (MD) simulations provides the opportunity to investigate some aspects of the interaction. While molecular dynamics simulations, present in the literature, have provided important information about the dynamic structural behavior of the pMHC-TCR complex, most of them have modeled the pMHC-TCR complex in solution, whereas in physiological conditions the complex is bound to the membrane. Moreover, due to system dimension, only short simulations (about 15 ns) have been performed .
In this project we plan four independent Md simulations of the pMHC-TCR complex anchored in two opposite membranes on time-scale of microseconds. Such data should allow to analyze the structural and conformational behavior in response to the binding of different peptides to MHC binding groove and to compare such a behavior with respect with different TCRs interacting with the same pMHC complex.
The aim of this project is to clarify the role of peptide-induced conformational change of the MHC groove at an atomistic viewpoint as well as to characterize the role of different "clonotype" TCRs in the antigen recognition.
Due to the extremely high dimension and complexity of the system, such a work is well beyond the computational limit of standard MD simulations, thus requiring an computational power available by means of petascale HPC resources only.
Such an effort will provide an unprecedented description of one of the most investigated but still obscure mechanism regulating the immunological response.
Our work will be the first computational study involving the pMHC/TCR in a lipids environment, where both the peptide and the TCR will be mutated. Although several experimental data are available, no previous study was done in order to analyze the structural and dynamical characterization of different complexes considering different variables such as the lipids compositions, peptide sequence and TCR. The possibility to characterize the different interactions in the pMHC/TCR complex could establish a new frontier in the modern immunology, and a different point of view to understand the mechanism involved in the T cell recognition and its response to a specific antigen. Due to the high interest in the scientific community about the immune response especially for the still unanswered "whys" of autoimmune diseases and the alloreactivity, this work can help to unveil these unknown and fundamental processes occurring in the immunological system.