Lundbeckfonden - Lundbeck Foundation Junior Group Leader Fellowship - Investigation of the Molecular Basis of Neurological Diseases Related to Ion Pumps Using Molecular Simulations

Project: Research

Project Details

Description

The goals of this project are 1) to discover voltage-sensing elements in ion pumps, 2) todeduce their ion-selectivity mechanisms and ion access pathways and 3) to understand themolecular and structural basis of neurological diseases caused by mutations in ion pumps.
The achievement of these goals will provide unprecedented insight into the ion-pumpingmechanism and will enable direct visualization of operation of the molecular machine whilesimultaneously providing quantitative thermodynamic descriptions. The simulations willsolve decades-old problems such as ion-selectivity and voltage-sensing mechanisms in thefield of ion pumps in particular, and active transmembrane transport in general. Knowledgeof molecular mechanisms will not only help unravel the molecular basis of neurologicaldisorders linked to ion pumps, but also other important clinical targets such as multidrugeffluxpumps in antibiotic resistant bacteria. The project aligns with modern biology’sendeavor to understand the fundamental physical and chemical phenomena that drive theoperation of cellular molecular machinery.
Ion pumping proteins use chemical energy for the uphill transport of ions across cellularmembranes. Life is unsustainable without pumps and their partial impairment causesdisease. Molecular dynamics (MD) simulations will be used to investigate ion pumps bothin their natural electrical and thermal environments on the molecular level, which has notbeen accomplished before. Simulations will be compared with experimental measurementsto test accuracy and predictive ability through collaborations with experimental groupsspecializing in biochemical and biophysical measurements. Our recent report, where MDsimulations were combined with electrophysiology leading to the discovery of new ionpathways in the Na+-K+ ATPase pump (Poulsen, Khandelia et. al. Nature, 2010, 467, 99) istestimony to the feasibility, potential impact and multidisciplinary nature of the project.
StatusFinished
Effective start/end date01/01/201231/12/2019