Class II major histocompatibility complex (MHC)
proteins are involved in initiation of immune responses to foreign
antigens via presentation of
peptides to receptors of CD4(+) T-cells. An analogous presentation of self-
peptides may lead to
autoimmune diseases, such as
rheumatoid arthritis (RA). The
glycopeptide fragment CII259-273, derived from
type II collagen, is presented by A(q) MHCII molecules in the mouse and has a key role in development of
collagen induced arthritis (CIA), a validated model for RA. We have introduced
hydroxyethylene amide bond isosteres at the Ala(261)-Gly(262) position of CII259-273.
Biological evaluation showed that A(q) binding and T cell recognition were dramatically reduced for the modified
glycopeptides, although static models predicted similar binding modes as the native
type II collagen fragment. Molecular dynamics (MD) simulations demonstrated that introduction of the
hydroxyethylene isosteres disturbed the entire hydrogen bond network between the
glycopeptides and A(q). As a consequence the
hydroxyethylene isosteric
glycopeptides were prone to dissociation from A(q) and unfolding of the β1-helix. Thus, the isostere induced adjustment of the hydrogen bond network altered the structure and dynamics of A(q)/
glycopeptide complexes leading to the loss of A(q) affinity and subsequent T cell response.