Rheumatoid factor (RF) proteins are present in the tissue of individuals who suffer from the autoimmune disease rheumatoid arthritis, which can be extremely painful and disabling. RF binds to specific epitopes in the IgG class of antibodies, forming an immune complex, which initiates an inflammatory response and eventually results in tissue damage of diseased joints. The profile of the glycans obtained from immunoglobulins (IgGs) collected from inflammatory diseased tissue can be significantly different from """"""""normal"""""""" IgGs. Notably, RF binds to Fc only when the terminating galactosyl residues are no longer present, as seen in the Fc/IgG-RF/IgM crystal structure complex. This change in glycan sequence correlates with disease symptoms.
The specific aim of this proposal is to gain a better understanding of the structure-activity relationship between human immunoglobulin G isotype 4 (IgG4) antibody and human IgM rheumatoid factor through the use of theoretical tools. This will be accomplished by achieving the following four goals: 1) Development of a suitable computational model for the IgG4 cleavage fragment (Fc), 2) Quantifying the extent of the Fc glycan mobility, 3) Determining the effect of degalactosylation on the Fc fragment structure and dynamics, and 4) Exploring the influence of point mutations in the Fc domain in close proximity to the glycan. The AMBER program suite will be used to perform minimization and dynamics on the Fc fragment. Due to the similarities between all antibody types this research may have implications beyond the specific Fc/IgG4-RF/IgM immune complex.
