|
|||||
|
|
Cumulative hydropathic topology of a voltage-gated sodium channel at atomic resolution |
|
| Authors: | Markos N. Xenakis Dimos Kapetis Yang Yang Jordi Heijman Stephen G. Waxman Giuseppe Lauria Catharina G. Faber Hubert J. Smeets Ronald L. Westra Patrick J. Lindsey |
| Affiliation: | 1. Department of Genetics and Cell Biology, Section Clinical Genomics, Maastricht University, Maastricht, the Netherlands;2. Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy;3. Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University College of Pharmacy, West Lafayette, Indiana, USA Purdue Institute for Integrative Neuroscience, West Lafayette, Indiana, USA;4. Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands;5. Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut, USA Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, USA;6. Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy Department of Biomedical and Clinical Sciences "Luigi Sacco", University of Milan, Milan, Italy;7. Department of Neurology, Maastricht University Medical Center, Maastricht, the Netherlands;8. Department of Genetics and Cell Biology, Section Clinical Genomics, Maastricht University, Maastricht, the Netherlands School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, the Netherlands;9. Department of Data Science and Knowledge Engineering, Maastricht University, Maastricht, the Netherlands;10. Department of Genetics and Cell Biology, Section Clinical Genomics, Maastricht University, Maastricht, the Netherlands School for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, the Netherlands |
| Abstract: | Voltage-gated sodium channels (NavChs) are biological pores that control the flow of sodium ions through the cell membrane. In humans, mutations in genes encoding NavChs can disrupt physiological cellular activity thus leading to a wide spectrum of diseases. Here, we present a topological connection between the functional architecture of a NavAb bacterial channel and accumulation of atomic hydropathicity around its pore. This connection is established via a scaling analysis methodology that elucidates how intrachannel hydropathic density variations translate into hydropathic dipole field configurations along the pore. Our findings suggest the existence of a nonrandom cumulative hydropathic topology that is organized parallel to the membrane surface so that pore's stability, as well as, gating behavior are guaranteed. Given the biophysical significance of the hydropathic effect, our study seeks to provide a computational framework for studying cumulative hydropathic topological properties of NavChs and pore-forming proteins in general. |
| Keywords: | cumulative hydropathic effects hydrophobic gating NavAb scaling topology voltage-gated sodium channels |