Theory of Protein-Protein Association

描述（由申请人提供）：蛋白质-蛋白质结合的速率在许多基本生物过程中起关键作用，从酶催化/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关联率，仅给出蛋白质复合物的结构，并阐明蛋白质-蛋白质关联的机制。建议的研究重点是进一步发展和应用我们的过渡态理论的关联率。该理论的基础将通过过渡态的结构模型的发展得到加强，该模型具有更严格的统计力学基础，并明确说明了保持结合复合物的相互作用的短程性质。该理论将被应用到广泛的蛋白质系统，以测试其鲁棒性，并实现更好地理解静电增强的缔合速率。特别是对白细胞介素4（intedukin-4，IL-4）与IL-4结合蛋白相互作用的研究，将为IL-4拮抗剂的设计提供有价值的思路。替代参数化的泊松-玻尔兹曼静电计算的过渡态理论的预测的影响将进行评估。一个最佳的参数化将选择参考分子动力学模拟。通过这些进一步的发展和实例应用，过渡态理论将成为一个既定的方法，具有广泛的适用性，以研究蛋白质-蛋白质协会。该项目将通过操纵静电相互作用和设计干扰蛋白质-蛋白质相互作用的药物分子，为控制蛋白质功能奠定一些基础。

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.