Theoretical Studies of Antibody-Antigen Binding

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9506900 Sharp This research is directed at understanding the physical and chemical basis of specific antibody-antigen binding. The system for study consists of three antibody/protein complexes and four antibody/hapten complexes for which high resolution X-ray structures and binding data are available, plus data on binding differences for point amino acid mutations and hapten analogue binding. The study will focus on: 1) The role of solvation, including both electrostatic and hydrophobic interactions. 2)'Association entropy' changes arising from translational/rotational entropy loss upon binding, and conformational entropy changes. A combination of theoretical approaches will be used, in order to develop computationally feasible yet quantitative methods for calculating binding energies. Electrostatics will be treated using a continuum treatment of solvent with an atomic detail representation of the molecule, using the Finite Difference Poisson-Boltzmann (FDPB)method. Dynamic aspects will be handled by a method which combines the FDPB method with molecular mechanics (FDPB/MD). Hydrophobic interactions will be treated using surface free energy relationships. Conformational entropy changes will be assessed by quasi-harmonic analysis using dynamics. %%% This research will have general significance both for understanding how antibodies recognize (bind tightly) to specific antigens, and for biological recognition in general. The specific recognition of antigens by antibodies is a fundamental part of the immune response. Also the antibody-antigen interaction is a paradigm for molecular recognition in biology. specific binding is also a key requirement of effective inhibitors and drugs. The ability to calculate binding energies from antibody-antigen structures has significance for indentifying the driving force for binding, the origins of specificity, the role of antigen-antibody complementarity and the intrinsic antigenicity of surface groups, and for the design of inhibitors and drugs. ***