Theory of Protein-Protein Association

描述（由申请人提供）：蛋白质与小分子和大分子靶标的结合是生物学的中心。这些关联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。该项目的长期目标是通过理论、模拟和实验确定关联率和机制。在过去的资助期间的努力已经在瞬态复杂理论中达到高潮。当分子相对刚性时，这种计算方法允许解决蛋白质缔合问题，使得整体平移/旋转扩散是速率决定的。预设项目旨在解决更具挑战性的问题，其中构象变化与缔合过程密切相关，并且对生物功能至关重要。具体目标是确定三类系统的速率常数和机制：（1）蛋白质-蛋白质缔合;（2）蛋白质-配体结合;和（3）位点特异性蛋白质-DNA结合。 该研究将整合计算和实验，并带来方法上的突破，使计算蛋白质缔合速率常数的构象变化的现实建模。所获得的知识将揭示重要的蛋白质功能，并提供广泛的机制见解。

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.