Computational studies of P-type ATPase ion pumps

钠钾泵和钙泵是像“分子机器”一样起作用的蛋白质。它们利用三磷酸腺苷（ATP）的水解作为能量来源来做功，并积极地将离子转运穿过生物膜。这些泵对生命至关重要。例如，钠-钾泵恢复我们体内所有细胞所需的这些离子的浓度，人体近30%的ATP被这种蛋白质消耗。该建议的目标是阐明一般的基本原则，在原子水平上使用理论和计算机模拟的离子泵的功能。了解ATP驱动离子泵的一般原理，可以从分子结构的角度解决基本问题。这个多学科的研究项目，在生物学，物理学，化学和计算的关系，提供了一个很好的机会来捕捉高中学生的想象力和兴趣。外联活动将寻求通过大学学者计划（CSP）向代表性不足的芝加哥公立学校高中学生传播和交流有关定量生物学和物理学的教育机会，以鼓励大学入学。该提案的总体目标是阐明在原子水平上使用理论，分子动力学模拟和计算科学方法来管理P型ATP酶膜结合离子泵功能的一般基本原理。P型ATP酶形成一个大的膜蛋白超家族，其命名是因为它们能够利用三磷酸腺苷（ATP）的水解作为化学自由能的来源，以主动地将底物逆着它们的电化学电势梯度运输穿过生物膜。该研究计划旨在回答一些关于这些泵功能的一般原理的引人注目的生物学问题。我们的工作集中在两个典型的系统-钠-钾和钙泵，理想的研究的基本原则，管理的P型ATP酶的功能。一个变革性的计算方法，整合理论，算法，模拟方法，机器学习技术和计算科学将产生解决有关复杂的生物分子机器的主要生物学问题。这项工作将作为未来工作的路线图，旨在定量表征其他ATP驱动的“生物分子机器”的功能，并将有助于生物启发人工泵的设计。该奖项反映了NSF的法定使命，并已被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

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.