Computational studies of P-type ATPase ion pumps

钠钾泵和钙泵是像“分子机器”一样的蛋白质。它们利用三磷酸腺苷（ATP）的水解作为能量来源来完成工作并积极地在生物膜上运输离子。这些泵对生命至关重要。例如，钠钾泵恢复了我们体内所有细胞所需的离子浓度，人体近30%的ATP被这种蛋白质消耗。该建议的目标是利用理论和计算机模拟阐明在原子水平上控制这种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。这个跨学科的研究项目，在生物学，物理学，化学和计算的联系，提供了一个很好的机会来捕捉高中学生的想象力和兴趣。外展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生传播和交流关于定量生物学和物理学的教育机会，以鼓励大学入学。本提案的总体目标是利用理论、分子动力学模拟和计算科学的方法，阐明在原子水平上控制p型atp酶膜结合离子泵功能的一般基本原理。p型ATP酶形成了一个大的整体膜蛋白超家族，因其利用三磷酸腺苷（ATP）水解作为化学自由能来源的能力而得名，以对抗其电化学电位梯度在生物膜上主动运输底物。该研究计划旨在回答一些关于控制这些泵功能的一般原理的令人信服的生物学问题。我们的工作集中在两个典型的系统-钠钾和钙泵，理想的研究控制p型atp酶功能的基本原理。整合理论、算法、模拟方法、机器学习技术和计算科学的变革性计算方法将产生，以解决有关复杂生物分子机器的主要生物学问题。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，并将有助于设计受生物启发的人工泵。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.