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 A(q) class II MHC
protein. The isostere-modified
glycopeptides showed varying and unexpectedly large losses of A(q) binding that could be linked to the dynamics of the system. Molecular dynamics (MD) simulations revealed that the backbone of CII259-270 and the A(q)
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 hydrogen bonds were strongly coupled to each other; the loss of one hydrogen-bond interaction had a profound effect on the entire hydrogen-bonding network. The A(q) binding data revealed that an
ethylene isostere
glycopeptide unexpectedly bound more strongly to A(q) than the corresponding (E)-
alkene, which is in contrast to the trend observed for the other isosteres. Analysis of the MD trajectories revealed that the complex conformation of this
ethylene isostere was structurally different and had an altered molecular interaction pattern compared to the other A(q)/
glycopeptide complexes. The introduced
amide-bond isosteres also affected the interactions of the
glycopeptide/A(q) complexes with
T-cell receptors. The dynamic variation of the patterns and strengths of the hydrogen-bond interactions in the class II MHC system is of critical importance for the class II MHC/
peptide/TCR signaling system.