Geometrical Insights into the Process of Antibody Aggregation

IgE antibodies bound to cell-surface receptors, Fc RI, crosslink through the binding of antigens on the cell surface. This formation of aggregates is what stimulates mast cells and basophils in order to initiate degranulation, resulting in an allergic response. Nearly 1,500 Americans die each year from anaphylactic shock predicated by aggregation. Experimental studies have shown the spatial organization of the aggregated IgE-Fc RI complexes affect transmembrane signaling that initiates allergic response. There are many factors that can affect the shape and size of aggregates. However, one critical factor may be the conformational structure of the antigen (ligand). This structure can affect the number of receptors that can bind to a single ligand, e.g., the valency of the ligand. For example, a common hay fever antigen has a valency of four where as the common shrimp antigen has a valency of eighteen. 3-D simulation of hundreds of antibodies aggregating can be computationally infeasible. However, we present methods based on robotic representations of molecular structures and Monte Carlo simulation that provide 3-D details of aggregate formation. In this paper, we demonstrate the utility of our methods on ligands of different valences: a bivalent DCT2-cys (DCT) and a trivalent fibritin trimer (DF3). We show that we can capture experimentally measured properties while enabling a detailed look into the geometry of aggregation formation.