The free energy landscapes governing the function of complex biomolecular machines

控制复杂生物分子机器功能的自由能景观

• 批准号: 1640888
• 负责人: Benoit Roux
• 金额: $ 0.54万
• 依托单位: University of Chicago
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1640888&HistoricalAwards=false
• 关键词: free; energy; landscapes; governing; function

Complex macromolecular assemblies of proteins, nucleic acids and carbohydrates consume energy in order to perform specific biological functions. The concerted action of these "molecular machines" underlies all the activities of the living cell. Therefore, a better understanding of this machinery will allow us to answer fundamental questions about the biology of all organisms. The proteins associated with biological membranes are particularly remarkable. Proteins such as ion channels, transporters, pumps, receptors, kinases, and phosphatases play an essential role in controlling the bidirectional flow of material and information across the biological membrane, and as such, they are truly devices able to accomplish complex tasks. This project will use an extremely large allocation of computer time on the largest NSF-supported HPC system, Blue Waters, to gain a deep mechanistic perspective of protein function, linking structure to dynamics, by characterizing the free energy landscapes that govern key functional processes in these systems. Deliverables from the project include not only fundamental scientific insights about the systems under investigation, but also computational tools for investigating biomolecules, and the free distribution of software and extended computer scripts. All development work (parameters, software computer programs and scripts) will be made publicly available to the academic community.Some proteins can act as an electric pump, consuming ATP to carry charged ions against their electrochemical potential gradient, while some, like ion channels, simply allow selected ions to diffuse passively. Strong electrostatic interactions involving ions or charged residues are often implicated in the function of these systems. For example, at the heart of the molecular mechanism of the ATP-driven ionic pumps are fundamental processes of ion diffusion and binding to selective binding sites in the core of the protein. This project will use Blue Waters to investigate the selective ion binding processes in one important ATP-driven pumps: the Na+/K+-ATPase. It will also study the factors controlling the stability of the C-type inactivated state of the selectivity filter of the csA K+ channel, a non-conducting state of K+ channels of great physiological implications. In the proposed work, ATP-driven ion pumps, K+ channels, and Src tyrosine kinases will be studied within a unified computational perspective provided by free energy landscapes.

蛋白质、核酸和碳水化合物的复杂大分子组装体消耗能量以执行特定的生物功能。这些“分子机器”的协调行动是活细胞所有活动的基础。 因此，更好地了解这种机制将使我们能够回答有关所有生物体生物学的基本问题。 与生物膜相关的蛋白质尤其引人注目。 蛋白质如离子通道、转运蛋白、泵、受体、激酶和磷酸酶在控制物质和信息跨生物膜的双向流动中起着至关重要的作用，因此，它们是能够完成复杂任务的真正设备。 该项目将在最大的NSF支持的HPC系统Blue沃茨上使用极大的计算机时间分配，以获得蛋白质功能的深层机制视角，将结构与动力学联系起来，通过表征控制这些系统中关键功能过程的自由能景观。 该项目的成果不仅包括对正在研究的系统的基本科学见解，还包括用于研究生物分子的计算工具，以及软件和扩展计算机脚本的免费分发。 所有的开发工作（参数、软件计算机程序和脚本）都将向学术界公开。有些蛋白质可以充当电动泵，消耗ATP来携带带电离子对抗其电化学电位梯度，而有些蛋白质则像离子通道一样，只是让选定的离子被动扩散。涉及离子或带电残基的强静电相互作用通常涉及这些系统的功能。例如，ATP驱动的离子泵的分子机制的核心是离子扩散和结合到蛋白质核心中的选择性结合位点的基本过程。 本计画将使用Blue沃茨来研究一种重要的ATP驱动泵：Na+/K+-ATP酶中的选择性离子结合过程。它还将研究控制csA K+通道的选择性过滤器的C型失活状态的稳定性的因素，这是一种具有重大生理意义的K+通道的非传导状态。 在拟议的工作中，ATP驱动的离子泵，K+通道，Src酪氨酸激酶将在一个统一的计算自由能景观提供的角度进行研究。

项目成果

Chemical substitutions in the selectivity filter of potassium channels do not rule out constricted-like conformations for C-type inactivation

• DOI: 10.1073/pnas.1706983114
• 发表时间: 2017-10-17
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Li, Jing;Ostmeyer, Jared;Roux, Benoit
• 通讯作者: Roux, Benoit