Computational studies of P-type ATPase ion pumps

P型ATP酶离子泵的计算研究

• 批准号: 2309048
• 负责人: Benoit Roux
• 金额: $ 90万
• 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: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2309048&HistoricalAwards=false
• 关键词: Computational; studies; type; ATPase; ion

The sodium-potassium and the calcium pump are proteins acting like “molecular machines”. They use the hydrolysis of adenosine triphosphate (ATP) as a source of energy to perform work and actively transport ions across the biological membrane. These pumps are extremely important for life. For example, the sodium-potassium pump restores the concentration of those ions needed for all the cells in our body and almost 30% of a human's ATP is consumed by this protein. The goal of the proposal is to elucidate the general fundamental principles governing the function of such ion pump at the atomic level using theory and computer simulations. Understanding the general principle governing the mechanism of an ATP-driven ion pump addresses fundamental questions from the point of view of molecular structure. This multidisciplinary research project, at the nexus of biology, physics, chemistry, and computations, offers a great opportunity to capture the imagination and interest of high school students. Outreach activities will seek to disseminate and communicate education opportunities about quantitative biology and physics to underrepresented Chicago Public Schools high school students via the Collegiate Scholars Program (CSP) to encourage college enrollment. The overarching goal of this proposal is to elucidate the general fundamental principles governing the function of P-type ATPase membrane-bound ion pumps at the atomic level using theory, molecular dynamics simulations, and methods from computational sciences. P-type ATPases form a large superfamily of integral membrane proteins named for their ability to exploit the hydrolysis of adenosine triphosphate (ATP) as a source of chemical free energy to actively transport substrates against their electrochemical potential gradient across a biological membrane. The research plan is designed to answer a number of compelling biological questions about the general principles governing the function of these pumps. Our work focuses on two paradigmatic systems—the sodium-potassium, and the calcium pump, ideal for studying the fundamental principles governing the function of P-type ATPases. A transformative computational methodology, integrating theory, algorithms, simulation methods, machine-learning techniques and computational sciences will be generated to address major biological questions about complex biomolecular machines. The work will serve as a roadmap for future efforts aimed at quantitatively characterizing the function of other ATP-driven “biomolecular machines” and will help in the design of bioinspired artificial pumps.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

钠钾和钙泵是作用于“分子机”的蛋白质。他们使用三磷酸腺苷（ATP）的水解作为执行工作并在生物膜上积极运输离子的能源。这些泵对生活非常重要。例如，钠钾泵恢复了我们体内所有细胞所需的那些离子的浓度，并且该蛋白质消耗了几乎30％的人ATP。该提案的目标是阐明使用理论和计算机模拟在原子水平上控制这种离子泵功能的一般基本原理。从分子结构的角度来看，了解ATP驱动的离子泵机理的一般原理解决了基本问题。这个在生物学，物理学，化学和计算的联系的多学科研究项目提供了一个很好的机会，可以通过大学（COSS SPSS）（CSP）鼓励芝加哥公立学校的高中学生（CSSP）来捕捉和传播有关定量生物学和物理学的教育机会，以传播有关定量生物学和物理学的教育机会。该提案的总体目标是阐明使用理论，分子动力学模拟以及计算科学的方法，阐明了原子水平上P型ATPase膜结合离子泵功能的一般基本原理。 P型ATPases形成了整体膜蛋白的大型超家族，以探索三磷酸腺苷（ATP）水解的能力，作为化学自由能的水解来源，可以主动运输跨生物膜的电化学潜在梯度。该研究计划旨在回答有关管理我们工作的一般原则的许多计算问题，重点是两个范式系统 - 钠磷酸钠和钙泵，非常适合研究管理P-Type ATPases功能的基本原理。将生成一种变革性计算方法，整合理论，算法，模拟方法，机器学习技术和计算科学，以解决有关复杂生物分子机器的主要生物分子问题。这项工作将作为未来努力的路线图，旨在定量地表征其他ATP驱动的“生物分子机器”的功能，并将有助于设计生物启发的人工泵的设计。这项奖项反映了NSF的法定任务，并通过使用该基金会的知识分子和广泛的影响来评估CRITERIA CRITERIA。