The goals of our research in ion pumps (the Na K pump in particular) are:
- to discover voltage-sensing elements in ion pumps
- to deduce their ion-selectivity mechanisms and ion access pathways
- to unravel molecular mechanisms of regulation of the ion pump and
- to understand the molecular and structural basis of neurological diseases caused by mutations in ion pumps.
Ion pumping proteins use chemical energy for the uphill transport of ions across cellular membranes. Life is unsustainable without pumps and their partial impairment causes disease. MD simulations will be used to investigate ion pumps both in their natural electrical and thermal environments on the molecular level, which has not been rarely accomplished before. Simulations will be compared with experimental measurements to test accuracy and predictive ability through collaborations with experimental groups specializing in biochemical and biophysical measurements. In a recent report, MD simulations were combined with electrophysiology leading to the discovery of new ion pathways in the Na+-K+ ATPase pump (Poulsen, Khandelia et. al. Nature, 2010, 467, 99).
Poulsen, H., Khandelia, H., Morth, J.P., Bublitz, M., Mouritsen, O.G., Egebjerg, J. and Nissen, P. (2010) Neurological disease mutations compromise a C-terminal ion pathway in the Na(+)/K(+)-ATPase. Nature, 467, 99-102. DOI: 10.1038/nature09309
Poulsen, H., Nissen, P., Mouritsen, O. G., and Khandelia, H. (2012) Protein Kinase A (PKA) Phosphorylation of Na+/K+-ATPase Opens Intracellular C-terminal Water Pathway Leading to Third Na+-binding site in Molecular Dynamics Simulations, J. Biol. Chem. 287, 15959-15965.
Kopec, W., Loubet, B., Poulsen, H., and Khandelia, H. (2014) Molecular mechanism of Na(+),K(+)-ATPase malfunction in mutations characteristic of adrenal hypertension, Biochemistry 53, 746-754.
Mahmmoud, Y. A., Kopec, W., and Khandelia, H. (2015) K+ Congeners That Do Not Compromise Na+ Activation of the Na+,K+-ATPase: HYDRATION OF THE ION BINDING CAVITY LIKELY CONTROLS ION SELECTIVITY, J. Biol. Chem. 290, 3720-3731.
Sahoo, S. K., Shaikh, S. A., Sopariwala, D. H., Bal, N. C., Bruhn, D. S., Kopec, W., Khandelia, H., and Periasamy, M. (2015) The N Terminus of Sarcolipin Plays an Important Role in Uncoupling Sarco-endoplasmic Reticulum Ca2+-ATPase (SERCA) ATP Hydrolysis from Ca2+ Transport, J. Biol. Chem. 290, 14057-14067.