Realistic simulation of the activation of voltage-gated ion channels

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 9; pp. 3335 - 3340
• Main Authors: Dryga, Anatoly, Chakrabarty, Suman, Vicatos, Spyridon, Warshel, Arieh
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 28-02-2012; National Acad Sciences
• Subjects: Algorithms; Allosteric Regulation; Biological Sciences; Computer Simulation; Electric current; Electric potential; Electrodes; Electrolytes; Energy; energy balance; Free energy; Ion Channel Gating; Ion channels; Ions; Kv1.2 Potassium Channel - chemistry; Kv1.2 Potassium Channel - metabolism; Membrane potential; Membrane Potentials; Modeling; Models, Chemical; Models, Molecular; Potassium - metabolism; Protein Conformation; Proteins; Simulation; simulation models; Solutions
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1121094109

Understanding the detailed mechanism of the activation of voltage-gated ion channels has been a problem of great current interest. Reliable molecular simulations of voltage effects present a major challenge because meaningful converging microscopic simulations are not yet available and macroscopic treatments involve major uncertainties regarding the dielectric constant used and other key features. The current work has overcome some of the above challenges by using our recently developed coarse-grained (CG) model in simulating the activation of the Kv1.2 channel. The CG model has allowed us to explore problems that cannot be addressed at present by fully microscopic simulations, while providing insights on some features that are not usually considered in continuum models, including the distribution of the electrolytes between the membrane and the electrodes during the activation process and thus the nature of the gating current. Furthermore, the clear connection to microscopic descriptions combined with the power of CG modeling offers a powerful tool for exploring the energy balance between the protein conformational energy and the interaction with the external potential in voltage-activated channels. Our simulations have reproduced the observed experimental trend of the gating charge and, most significantly, the correct trend in the free energies, where the closed channel is more stable at negative potential and the open channel is more stable at positive potential. Moreover, we provide a unique view of the activation landscape and the time dependence of the activation process.