Computational studies of P-type ATPase ion pumps

University Of Chicago, Chicago IL

Investigators

Abstract

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.