Molecular Mechanistic Studies of Antigen-Loading to MHCII Proteins for the Adaptive Immune Recognition by T Cells

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Major Histocompatibility Complex class II (MHCII) proteins are biomolecular machines in the immune system that are responsible for the correct loading and presentation of antigenic peptides to T cells; reversely, the dysfunction of these machines is associated with various classes of immune disorders, including allergy, autoimmunity, and immunodeficiency. Important insights into the molecular mechanism of antigen loading to MHCII have been enabled by a number of experimental and computational studies, including X-ray crystallography, NMR spectroscopy, and Molecular Dynamics (MD) simulations. Nevertheless, a molecular mechanistic understanding remains wanted of the detailed conformational dynamics necessary for antigen loading to MHCII, and how these dynamics can be modulated. Therefore, in the proposed research project hosted by Prof. Dr. Frank Noé at Freie Universität Berlin, we will computationally predict these conformational dynamics for phenotypic MHCII mutants and binding partners from an experimentally testable, atomically holistic perspective (i.e. of atoms in the context of entire proteins). To this end, we will establish a synergy between Markov State Modeling (MSM)-based adaptive sampling of MD simulations, protein-wide atomic interaction analyses, and alchemical free energy computations. The successful outcome of this project will be further facilitated through integration into a collaborative network of other excellent scientists, including the experimental group of Prof. Dr. Christian Freund at Freie Universität Berlin, who is an internationally leading expert investigating the molecular mechanism of MHCII antigen loading.