Immune Response to Environmental Factors: MD Simulations of Antibody Structure
EMSL Project ID
9607
Abstract
Immune Response to Environmental Factors: MD Simulations of Antibody StructureKarl N. Kirschnera and Robert J. Woodsb
aHamilton College, Clinton, NY 13323
bComplex Carbohydrate Research Center, University of Georgia, Athens, GA 30602
Abstract
The effects of environmental allergens may be divided into three categories, namely, suppression of the immune response, induction of autoimmune diseases, and stimulation of allergic or asthmatic reactions.
Chemical hypersensitivity, which is related to allergy, has become an alarmingly frequent problem, as our natural environment becomes increasing contaminated with low levels of industrial pollutants. The immune system has a well-developed defense response to biological pathogens, such as viruses or bacteria, but sometimes it responds too aggressively to trace levels of chemical toxicants (sulfur dioxide, metals, isocyanates, aromatics, smoke compounds) or to innocuous substances (dust, mold, or pollen). While an allergic reaction is often merely unpleasant (hay fever), hypersensitivity to toxicants can induce life-threatening diseases, such as angioedema and anaphylaxis. Further, immune-complexes that remain too long in the body commonly accumulate in blood vessel walls, where they can cause inflammation leading to severe autoimmune diseases.
As a prelude to developing a detailed atomic level understanding of the immune response to environmental factors, we propose to establish the ability of molecular dynamic (MD) simulations to reproduce the experimentally known structures of antibody domains. Concurrently, we will use MD simulations to examine the influence that changes in the natural glycosylation state, associated with autoimmune disease, have on antibody structure and dynamics.
Antibody Structure and Dynamics
Antibodies exhibit a characteristic ?Y? shaped tertiary structure, composed of structurally conserved protein domains. The stem of the Y is called the Fc region, while the arms are called Fab regions. The Fc and Fab regions are linked together with short peptidic hinges. The majority of an antibody?s flexibility arises either from large magnitude, low frequency hinge motions or low magnitude mid frequency motions within the domains. These motions aid the antibody in binding to antigens and to Fc-receptors, such as FcεRI on mast cells.
The antibodies in patients with rheumatoid arthritis are known to display altered carbohydrate sequences in the Fc core. These changes may alter the overall shape and dynamics of the Fc region. Because the Fc interacts specifically with receptor proteins, alterations in the shape of dynamics of the Fc region have been implicated in altered immune responses and in certain autoimmune diseases, such as rheumatoid arthritis [1].
This project will investigate the ability of MD simulations to reproduce the structure of antibody Fc domains, and further will examine the effect that variation in N-glycosylation (the covalent linking of a complex carbohydrate to an asparagine side chain) has on Fc structure and dynamics.
References
1. Lee, D.M., et al. Science 297 (2002) 1689.
Project Details
Project type
Capability Research
Start Date
2004-07-14
End Date
2007-06-07
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members