Computational studies of P-type ATPase ion pumps

钠钾和钙泵是一种蛋白质，它们的行为就像“分子机器”。它们利用三磷酸腺苷(ATP)的水解作为能量来源来做功，并积极地将离子传输到生物膜上。这些泵对生命极其重要。例如，钠钾泵可以恢复人体内所有细胞所需的离子浓度，人体内近30%的三磷酸腺苷被这种蛋白质消耗。该提案的目的是通过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则。理解控制三磷酸腺苷驱动的离子泵机制的一般原理从分子结构的角度解决基本问题。这个多学科的研究项目，结合了生物、物理、化学和计算，提供了一个很好的机会来激发高中生的想象力和兴趣。外展活动将寻求通过大学生学者计划(CSP)向代表性不足的芝加哥公立学校高中生传播和交流有关数量生物学和物理学的教育机会，以鼓励大学入学。这项提议的首要目标是利用理论、分子动力学模拟和计算科学的方法在原子水平上阐明控制P型ATPase膜结合离子泵功能的一般基本原理。P型ATPase是一个完整的膜蛋白超家族，能够利用三磷酸腺苷(ATP)的水解作为化学自由能的来源，以对抗底物在生物膜上的电化学势梯度而活跃地运输底物。该研究计划旨在回答一些引人注目的生物学问题，这些问题涉及管理这些泵功能的一般原则。我们的工作集中于两个聚合系统-钠-钾和钙泵，这是研究P型ATPase功能的基本原理的理想选择。将产生一种革命性的计算方法，整合理论、算法、模拟方法、机器学习技术和计算科学，以解决关于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，并将有助于设计生物灵感人工泵。这一奖项反映了NSF的法定使命，并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，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.