The Structural Immunology Section investigates molecular recognition in antibody complexes with proteins as model systems to elucidate the general principles of protein target recognition by antibodies. We are using a comparative approach with a set of structurally and functionally related monoclonal antibodies, isolated during the evolution of the antibody immue response to a structurally defined protein antigen, in order to address the following questions about molecular recognition: (i) What structural features are predictive of complex association rates, stabilities, and thermodynamics? How do these functional parameters interrelate? (ii) What roles do electrostatic interactions, hydrophobic interactions, and water play in these processes? (iii) What structural features are predictive of specificity, or cross-reactivity with other antigens? (iv) What structural mechanisms are affected by somatic mutations during the process of antibody affinity maturation as the immune response progresses? (v) What is the influence of engineered constant region segments on binding kinetics and thermodynamics? The results to date have provided new paradigms on the mechanism of antibody-antigen binding, and in addition have provided new methodology for examining these interactions. The thermodynamic studies have revealed properties which we believe to be predictive of binding characteristics including long term complex stability and likely cross-reactivity with related antigens, and we are developing a protocol for assessing these properties which would be valuable in selection of lead therapeutic antibodies. The insight(s) gained by analyses of complex kinetics and thermodynamics provide a framework and rationale for design of antibodies of predefined specificity, and will also lead to better strategies for structure-based drug design and selection of lead compounds in molecular targeting efforts. It also provides a framework for understanding binding of other complexes, including as the HDM2 inhibitors of tumor suppressor p53 protein currently in progress in my group, and chaperone binding to receptors in collaboration with Dr. Wang's group. We are also planning future investigations on the ubiquitin pathway.
NIH ExPorter
NIH ExPorter