Antibodies are essential recognition elements of the immune system, which bind tightly and specifically to various antigens to block their activity or to mark them for destruction. Antibodies are increasingly used as diagnostic tools and therapeutic drugs, and an important component of the antibody design/engineering process is the availability of high quality three-dimensional structure of antibody–antigen complexes. X-ray crystallography provides the most accurate and detailed data on protein structure and interactions, however co-crystallization of antibody–antigen complexes remains a major challenge, and the number of antibody structures determined in complex with their antigens is still relatively small.
By contrast, computational modeling provides a fast and inexpensive route for generating structural models for such complexes. The variable domains (Fvs) of the heavy and light chain are of special interest in computational modeling, as they typically impart most or all of the specificity of an antibody for its antigen target. Our modeling protocol takes into consideration the most updated scientific knowledge of antibody–antigen interactions as well as conformational flexibility of the CDR region (especially the H3 loop), and utilizes state-of-the-art docking software tools to find the relative transformation and conformation of the antibody and antigen involved in energetically favorable complex formation. The general procedures are: First, a rigid body global search is performed and geometrically plausible antibody–antigen complex models are generated. In this process, user-defined restraints (obtained from experimental data) can be applied to limit the search space. The resulting models are scored and ranked using a scoring function, developed specifically for antibody systems. The best-scored structures are then clustered and representatives of the largest clusters are selected for structural optimization by energy minimization before being presented to the customer.