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Unraveling the strokes of ion transporters in computers
SeRC researchers in the molecular simulation community have been able to use molecular simulations to track the first-ever complete cycle of intermediate states as voltate-gated ion channels open in response to a nerve signal (1), something that has important implications for future drug design. Similarly, we have been the first to show that there are multiple separate “allosteric” binding sites that either amplify (potentiate) or decrease (inhibit) the response (2,3), which is the reason why we are aroused by some drugs but fall asleep from others. In addition, we have ongoing work that has shown that simulations can be used to predict the effects of mutations. Some of the greatest current challenges are to find ways to use this knowledge in order to design better anesthetics or even drugs that can be used to treat addiction disorders such as alcoholism
SeRC has been a critical factor in this success, particularly since it has enabled long-term close collaborations between computational and applied research, both of which have resulted in several high-impact publications and helped achieve internationally leading competence for membrane protein simulations in Stockholm.
• Henrion, U., Renhorn, J., Börjesson, S.I., Nelson, E.M., Schwaiger, C.S., Bjelkmar, P., Wallner, B., Lindahl, E.†, Elinder, F†. (2012) "Tracking a complete voltage-sensor cycle with metal-ion bridges", Proc. Natl. Acad. Sci. U S A 109:8552-7
2. Howard, R.J., Murail, S., Ondricek, K.E., Corringer, P.-J., Lindahl, E., Trudell, J.R., Harris, R.A. (2011) "Structural basis for alcohol modulation of a pentameric ligand-gated ion channel", Proc. Natl. Acad. Sci. USA 108:12149-12154
• Murail, S., Howard, R.J., Brömstrup, T., Bertaccini, E.J., Harris, R.A., Trudell, J.R., Lindahl, E. (2012) "Molecular mechanism for the dual alcohol modulation of Cys-loop receptors", PLoS Comput. Biol 8: e1002710
• Nyblom, M., H. Poulsen, P. Gourdon, L. Reinhard, M. Andersson, E. Lindahl, N. Fedosova, and P. Nissen. (2013) "Crystal structure of Na+, K(+)-ATPase in the Na(+)-bound state." Science 342:123-127
• Andersson, M., D. Mattle, O. Sitsel, T. Klymchuk, A. M. Nielsen, L. B. Moller, S. H. White, P. Nissen, and P. Gourdon. (2014) "Copper-transporting P-type ATPases use a unique ion-release pathway." Nature Struct. Mol. Biol. 21:43-48