Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

95-POS Board 15 MHC Class II Complexes Sample Intermediate States Along the Peptide Exchange Pathway Sebastian Stolzenberg 2 , Marek Wieczorek 1 , Jana Sticht 1 , Sebastian Günther 1,3 , Christoph Wehmeyer 2 , Zeina El Habre 1 , Miguel Álvaro-Benito 1 , Frank Noé 2 , Christian Freund 1 . 2 Computational Molecular Biology Group, Institute for Mathematics, Freie Universität Berlin, Berlin, Berlin, Germany, 1 Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Berlin, Germany, 3 Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA. The presentation of peptide-MHCII complexes (pMHCIIs) for surveillance by T cells is a well- known immunological concept in vertebrates, yet the conformational dynamics of antigen exchange remain elusive. By combining NMR-detected H/D exchange with Markov modelling analysis of an aggregate of 275 microseconds molecular dynamics simulations, we reveal that a stable pMHCII spontaneously samples intermediate conformations relevant for peptide exchange. More specifically, we observe two major peptide exchange pathways: the kinetic stability of a pMHCII’s ground state defines its propensity for intrinsic peptide exchange, while the population of a rare, intermediate conformation correlates with the propensity of the HLA- DM-catalysed pathway. Helix-destabilizing mutants designed based on our model shift the exchange behaviour towards the HLA-DM-catalysed pathway and further allow us to conceptualize how allelic variation can shape an individual’s MHC restricted immune response.

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