Dynamics Determine Signaling in a Multicomponent System Associated with Rheumatoid Arthritis

Strategies
that target multiple components are usually required
for treatment of diseases originating from complex biological systems.
The multicomponent system consisting of the DR4 major histocompatibility
complex type II molecule, the glycopeptide CII259–273 from
type II collagen, and a T-cell receptor is associated with development
of rheumatoid arthritis (RA). We introduced non-native amino acids
and amide bond isosteres into CII259–273 and investigated the
effect on binding to DR4 and the subsequent T-cell response. Molecular
dynamics simulations revealed that complexes between DR4 and derivatives
of CII259–273 were highly dynamic. Signaling in the overall
multicomponent system was found to depend on formation of an appropriate
number of dynamic intramolecular hydrogen bonds between DR4 and CII259–273,
together with the positioning of the galactose moiety of CII259–273
in the DR4 binding groove. Interestingly, the system tolerated modifications
at several positions in CII259–273, indicating opportunities
to use analogues to increase our understanding of how rheumatoid arthritis
develops and for evaluation as vaccines to treat RA.