Theoretical Studies of Antibody-Antigen Binding

9506900 Sharp本研究旨在了解特异性抗体-抗原结合的物理和化学基础。 研究系统由三种抗体/蛋白质复合物和四种抗体/半抗原复合物组成，其中高分辨率X射线结构和结合数据可用，加上点氨基酸突变和半抗原类似物结合的结合差异数据。本研究将集中在：1）溶剂化的作用，包括静电和疏水相互作用。 2.结合时平移/旋转熵损失引起的“缔合熵”变化和构象熵变化。 将使用理论方法的组合，以开发计算结合能的计算可行的定量方法。 静电将使用溶剂的连续处理与分子的原子细节表示，使用有限差分泊松-玻尔兹曼（FDPB）方法。 动态方面将处理的方法，结合FDPB方法与分子力学（FDPB/MD）。 疏水相互作用将使用表面自由能关系处理。 构象熵变将通过使用动力学的准调和分析进行评估。 这项研究对于理解抗体如何识别（紧密结合）特定抗原以及一般的生物识别都具有普遍意义。 抗体对抗原的特异性识别是免疫应答的基本部分。 抗体-抗原相互作用也是生物学中分子识别的范例。 特异性结合也是有效抑制剂和药物的关键要求。 从抗体-抗原结构计算结合能的能力对于识别结合的驱动力、特异性的起源、抗原-抗体互补性的作用和表面基团的内在抗原性以及抑制剂和药物的设计具有重要意义。 ***

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. ***