Conformational Ensembles from Experimental Data and Computer Simulations

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Conformational Ensembles from Experimental Data
and Computer Simulations Poster Abstracts
132
95-POS Board 15
MHC Class II Complexes Sample Intermediate States Along the Peptide Exchange
Pathway
Sebastian Stolzenberg2 , Marek Wieczorek1, Jana Sticht1, Sebastian Günther1,3, Christoph
Wehmeyer2 , Zeina El Habre1, Miguel Álvaro-Benito1, Frank Noé 2, Christian Freund1.
2Computational Molecular Biology Group, Institute for Mathematics, Freie Universität Berlin,
Berlin, Berlin, Germany, 1Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie
Universität Berlin, Berlin, Berlin, Germany, 3Institute 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.