Protein Complexes From Md Simulations: The Rope-Pulling Game Of Tapasin And Histocompatibility Molecules

Using multi-microsecond all-atom molecular dynamics (MD) simulations in explicit solvent, we characterized the association between protein tapasin and major histocompatibility complex class I (MHC I) molecules, two key players of the antigen-processing pathway. MHC I molecules are proteins that present peptide epitopes to cytotoxic T cells and hence are crucial to the mammalian adaptive immune response. Due to a lack of structural data on the tapasin / MHC I complex, the molecular events taking place during peptide loading onto MHC I were not well understood. We show that tapasin not only acts as a chaperone that stabilizes the MHC I structure: it also catalyzes the exchange of abundant non-specific peptides against the rare, immunodominant ones. This selection of high-affinity antigens from the vast pool of cytosolic degradation products is the result of a molecular game of rope-pulling: tapasin pulls on a region (α2-1) of the peptide binding groove of MHC I to open it, while the peptide simultaneously tries to close the groove. Low-affinity peptides “lose” this challenge and are exchanged until, eventually, a high-affinity contender binds to and closes the groove, thereby initiating complex break-down. Properly loaded MHC I molecules then migrate to the cell surface, where recognition by T-cell receptors takes place. Our simulations explain experimental kinetics and mutagenesis data, and represent the first in-depth, atomic-level study of the mechanism underlying the peptide-loading complex (PLC), an important step towards a better understanding of adaptive immunity.