Theory of Protein-Protein Association

描述(申请人提供)：蛋白质与小分子和大分子靶标的联系是生物学的中心。这些联合过程的速率和机制构成了基础知识，并为设计治疗剂提供了途径。这个项目的长期目标是通过理论、模拟和实验来确定关联率和机制。前几个资金期的努力在瞬变-复杂理论中达到顶峰。这种计算方法使蛋白质结合问题能够在分子相对刚性时得到解决，因此整体的平移/旋转扩散是速率决定的。这个预设的项目旨在解决一个更具挑战性的问题，在这个问题中，构象变化与缔合过程密切相关，对生物功能至关重要。其具体目标是确定三类系统的速率常数和机制：(1)蛋白质-蛋白质结合；(2)蛋白质-配体结合；(3)特定部位蛋白质-DNA结合。 这项研究将把计算和实验结合起来，并带来方法学上的突破，使计算蛋白质缔合速率常数的构象变化能够进行真实的建模。所获得的知识将阐明重要的蛋白质功能，并提供广泛的机械洞察力。

DESCRIPTION (provided by applicant): The association of proteins with small molecules and macromolecular targets is at the center of biology. The rates and mechanisms of these association processes constitute fundamental knowledge and provide avenues for designing therapeutic agents. The long-term objective of this project is the determination, via theory, simulation, and experiment, of association rates and mechanisms. Efforts in the pervious funding periods have culminated in the transient-complex theory. This computational methodology has allowed the protein association problem to be solved when the molecules are relatively rigid so that overall translational/rotational diffusion is rate- determining. The preset project aims to tackle the much more challenging problem where conformational change is closely coupled with the association process, and essential for biological function. The specific aims are the determination of rate constants and mechanisms for three classes of systems: (1) protein-protein association; (2) protein-ligand binding; and (3) Site-specific protein-DNA binding. The research will integrate computation and experiment, and bring methodological breakthroughs that enable realistic modeling of conformational changes in calculating protein association rate constants. The knowledge gained will shed light on important protein functions and offer broad mechanistic insights.