The free energy landscapes governing the function of complex biomolecular machines

蛋白质、核酸和碳水化合物的复杂大分子组合需要消耗能量来执行特定的生物功能。这些“分子机器”的协同行动构成了活细胞所有活动的基础。因此，对这一机制的更好理解将使我们能够回答关于所有有机体的生物学的基本问题。与生物膜相关的蛋白质尤其引人注目。离子通道、转运体、泵、受体、激酶和磷酸酶等蛋白质在控制物质和信息在生物膜上的双向流动中发挥着至关重要的作用，因此，它们确实是能够完成复杂任务的设备。这个项目将在NSF支持的最大的HPC系统Blue Waters上使用极大的计算机时间分配，通过表征支配这些系统中关键功能过程的自由能景观，获得蛋白质功能的深层机械观点，将结构与动力学联系起来。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，以及免费分发软件和扩展的计算机脚本。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。一些蛋白质可以充当电泵，消耗ATP来携带带电离子，以对抗其电化学势梯度，而另一些蛋白质，如离子通道，则只是允许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与这些系统的功能有关。例如，在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的选择性结合位置的基本过程。本项目将利用Blue Waters研究一种重要的ATP驱动泵：Na+/K+-ATPase中的选择性离子结合过程。它还将研究控制CsA K+通道选择性过滤器C型失活状态稳定性的因素，这是一种具有重要生理意义的K+通道的非传导状态。在这项拟议的工作中，将在自由能景观提供的统一计算视角下研究ATP驱动的离子泵、K+通道和Src酪氨酸激酶。

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.