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.

钠钾泵和钙泵是充当“分子机器”的蛋白质，它们利用三磷酸腺苷 (ATP) 的水解作为能量来源来进行工作并主动运输离子穿过生物膜。例如，钠钾泵可以恢复我们体内所有细胞所需的离子浓度，并且人体近 30% 的 ATP 都被这种蛋白质消耗。使用理论和计算机模拟在原子水平上阐明控制此类离子泵功能的一般基本原理，了解控制 ATP 驱动离子泵机制的一般原理从分子结构的角度解决了基本问题。结合生物学、物理、化学和计算的研究项目提供了一个激发高中生想象力和兴趣的绝佳机会，外展活动将寻求向弱势群体传播和交流有关定量生物学和物理学的教育机会。芝加哥公立学校高中生通过大学学者计划 (CSP) 鼓励大学入学 该提案的首要目标是阐明使用原子水平控制 P 型 ATP 酶膜结合离子泵功能的一般基本原理。理论、分子动力学模拟和计算科学方法形成了一个完整的膜蛋白大家族，因其利用三磷酸腺苷 (ATP) 水解作为来源的能力而得名。该研究计划旨在回答有关控制这些泵功能的一般原理的许多引人注目的生物学问题。钠钾泵和钙泵是研究 P 型 ATP 酶功能基本原理的理想选择，将产生一种集成理论、模拟方法、机器学习技术和计算科学的变革性计算方法，以解决重大生物学问题。关于复杂性的问题这项工作将作为未来努力的路线图，旨在定量描述其他 ATP 驱动的“生物分子机器”的功能，并将有助于设计仿生人工泵。该奖项反映了 NSF 的法定使命，并被认为是值得的。通过使用基金会的智力优势和更广泛的影响审查标准进行评估来获得支持。