(E)-Alkene and Ethylene Isosteres Substantially Alter the Hydrogen-Bonding Network in Class II MHC Aq/Glycopeptide Complexes and Affect T-Cell Recognition

The structural basis for antigen presentation by class II major histocompatibility complex (MHC) proteins to CD4+ T-cells is important for understanding and possibly treating autoimmune diseases. In the work described in this paper, (E)-alkene and ethylene amide-bond isosteres were used to investigate the effect of removing hydrogen-bonding possibilities from the CII259–270 glycopeptide, which is bound by the arthritis-associated murine Aq class II MHC protein. The isostere-modified glycopeptides showed varying and unexpectedly large losses of Aq binding that could be linked to the dynamics of the system. Molecular dynamics (MD) simulations revealed that the backbone of CII259–270 and the Aq protein are able to form up to 11 hydrogen bonds, but fewer than this number are present at any one time. Most of the strong hydrogen-bond interactions were formed by the N-terminal part of the glycopeptide, i.e., in the region where the isosteric replacements were made. The structural dynamics also revealed that hydr...