Theory of Protein-Protein Association

描述(由申请人提供)：蛋白质-蛋白质结合的速度在许多基本的生物过程中起着关键作用，从酶的催化/抑制到细胞因子对免疫的调节。我们的长期目标是可靠地预测结合率，只给出蛋白质复合体的结构，并阐明蛋白质-蛋白质结合的机制。建议的研究集中于我们关于关联率的过渡态理论的进一步发展和应用。通过发展过渡态的结构模型，该模型具有更严格的统计力学基础，并明确地解释持有束缚络合物的相互作用的短程性质，该理论的基础将得到加强。该理论将应用于广泛的蛋白质系统，以测试其稳健性，并实现对静电增强缔合率的更好理解。尤其是对IL-4与IL-4结合蛋白关系的研究将为IL-4拮抗剂的设计提供有价值的启示。将评估泊松-玻尔兹曼静电学计算的替代参数对过渡态理论预测的影响。将参考分子动力学模拟来选择最优的参数。通过这些进一步的发展和实例应用，过渡态理论将成为一种成熟的方法学，具有广泛的适用性，研究蛋白质-蛋白质相互作用。该项目将为通过操纵静电相互作用来控制蛋白质功能以及设计干扰蛋白质-蛋白质相互作用的药物分子奠定一些基本基础。

DESCRIPTION (provided by applicant): The rate of protein-protein association plays critical roles in many fundamental biological processes, ranging from enzyme catalysis/inhibition to regulation of immunity by cytokines. Our long-term objectives are to reliably predict association rates, given just the structures of protein complexes and elucidate the mechanisms of protein-protein association. The proposed research focuses on further developments and applications of our transition-state theory for the rate of association. The foundation of the theory will be strengthened through the development of a structural model for the transition state that has a more rigorous statistical mechanical basis and explicitly accounts for the short-range nature of the interactions holding the bound complex. The theory will be applied to a broad range of protein systems to test its robustness and achieve a greater understanding of electrostatic enhancement of association rates. In particular, the study on the association of intedukin-4 (IL-4) with IL-4-binding protein will provide valuable insight for the design of IL-4 antagonists. The impact of alternative parameterizations of Poisson-Boltzmann electrostatics calculations on the predictions of the transition-state theory will be evaluated. An optimal parameterization will be selected with reference to molecular dynamics simulations. Through these further developments and example applications, the transition-state theory will become an established methodology with broad applicability to the study of protein-protein associations. The project will lay some of the fundamental groundwork towards the control of protein function by manipulating electrostatic interactions and the design of drug molecules that interfere with protein-protein interactions.