Multiscale Modeling and Enhanced Sampling of Protein-Protein Recognition

该项目由化学系的生命过程化学计划、分子和细胞生物科学系的分子生物物理计划以及计算和数据使能的科学与工程计划共同资助。化学系的生命过程化学计划资助密歇根大学的查尔斯·L·布鲁克斯三世博士开发探索蛋白质-蛋白质相互作用的计算方法。蛋白质-蛋白质相互作用(PPI)构成了大多数生物过程的基础。对蛋白质-蛋白质相互作用的关键特征进行原子描述将产生巨大的好处，既可以建立对支持所有生命系统的过程的基本理解，也可以获得操纵和控制这些过程的能力。核磁共振波谱和X射线结晶学等实验方法可以揭示关键蛋白质-蛋白质相互作用的复合体和孤立单体的特征，但难以捕捉动态的、灵活的系统。分子动力学(MD)是解开这些实验测量的有用工具，并提供了一个详细的、动态的分子相互作用的视图。虽然蛮力分子动力学方法在研究单分子体系的动力学方面取得了重大进展，但由于这些体系的大尺寸、长时间尺度和高灵活性，它们在生物相关的PPI方面存在根本困难。该项目将开发、测试和应用计算方法，使MD研究能够探索病毒衣壳糖蛋白血凝素与假定的人类抗体模拟物的相互作用，以及细菌酸休克伴侣HdeA的伴侣活性。布鲁克斯博士将为一名博士后、研究生和一些本科生提供培训，并指导他们开发物理理论和模拟方法，以研究蛋白质与蛋白质的相互作用。此外，项目中开发的成果、方法和技术将通过教程和案例研究分发，并被整合到结构生物学多尺度建模工具(MMTSB)教程以及密歇根大学教授的课程中。该项目的具体成果将是以下方面的计算工具和方法：i)从粗粒度(CG)模拟预测依赖环境的核磁共振观察值；ii)开发专门用于重现观察到的蛋白质-蛋白质界面的可转移的CG相互作用势；iii)开发增强的采样方法，以有效地确定分子间相互作用的热力学和动力学性质。这项工作将集中在两个要求严格的基准案例上：病毒衣壳糖蛋白血凝素与假定的人类抗体模拟物的相互作用，以及细菌酸休克伴侣HdeA的伴侣活性。前者由于体系规模大(共600个氨基酸)而难度较大，而后者的相互作用是高度动态的，对体系pH敏感，涉及HdeA和底物蛋白的多个拷贝。

This project is jointly funded by the Chemistry of Life Processes Program in the Division of Chemistry, the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences and the Computational and Data-Enabled Science and Engineering program.The Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Charles L. Brooks III from the University of Michigan to develop computational methods to explore protein-protein interactions. Protein-protein interactions (PPIs) form the basis for most biological processes. An atomic description of the key features of protein-protein interactions will yield tremendous benefits in both establishing a fundamental understanding of the processes that support all living systems, and gaining the ability to manipulate and control those processes. Experimental approaches such as nuclear magnetic resonance spectroscopy (NMR) and X-ray crystallography can reveal features of interacting complexes and isolated monomers of key protein-protein interactions, but have difficulty capturing dynamic, flexible systems. Molecular dynamics (MD) is a useful tool to deconvolute these experimental measurements, and offers a detailed, dynamic view of molecular interactions. Although brute force MD approaches have made significant progress studying the dynamics of single molecule systems, they have fundamental difficulties with biologically relevant PPIs due to the large sizes, long time scales and high flexibility of these systems. This project will develop, test and apply computational approaches that enable MD studies to probe the interactions of the viral capsid glycoprotein Hemagglutinin with putative human antibody mimics, and the chaperone activity of the bacterial acid-shock chaperone HdeA. Dr. Brooks will provide training for a postdoc, graduate student and a number of undergraduates as well as mentoring them in the development of physical theories and simulation methods to study protein-protein interactions. Moreover, the findings, methods and techniques developed in this project will be distributed through tutorials and case studies to be integrated into the Multiscale Modeling Tools for Structural Biology (MMTSB) tutorials as well as into courses taught at the University of Michigan The specific outcome of the project will be computational tools and methods to i) predict environment-dependent NMR observables from coarse-grained (CG) simulations; ii) undertake the development of transferable CG interaction potentials that are specially designed for reproducing observed protein-protein interfaces; iii) undertake the development of enhanced sampling methods for efficient determination of thermodynamic and kinetic properties of intermolecular interactions. The work will focus on two demanding benchmark cases: the interactions of the viral capsid glycoprotein Hemagglutinin with putative human antibody mimics, and the chaperone activity of the bacterial acid-shock chaperone HdeA. The former system is difficult due to the large system size (600 amino acids total), while the interactions in the latter system are highly dynamic, sensitive to the system pH, and involve multiple copies of HdeA and substrate protein.