Ab Initio Studies on Voltage Gating of Ion Channels
EMSL Project ID
25433
Abstract
Abstract: The ab initio and DFT computations proposed here will clarify the mechanism of ion channel voltage gating. Ion channels are proteins in cell membranes that allow passage of K+, Na+, or Ca2+ ions (we are primarily concerned here with K+); in order to maintain control of the ion concentrations, the cell "gates" the channels by membrane depolarization (or addition of ligands, a channel type not part of this proposal). The importance of understanding this mechanism is extremely high, with large numbers of groups around the world engaged in studying them. The nerve impulse, and many diseases, cannot be understood without determining this mechanism. The mechanism is also extremely controversial, with contradictory proposals from several well known groups. We have proposed a somewhat unique mechanism. Regardless of which mechanism is correct, DFT or ab initio calculations will contribute to the solution of the problem. We will test gating mechanisms by a sequence of these calculations; we appear to have been the first group (but no longer the only one) to apply these calculational techniques to this question. We will study groups of amino acids in the known X-ray structures, optimizing the positions starting from the X-ray structures, including determing the positions of the water molecules and the hydrogen bonds. Hydrogen is not seen in the X-ray structures, and the water molecule positions are often ambiguous. However, these appear, based on our recently published study of the KcsA channel, to be the key to the structure at least of the closed state of the channel, and are well defined in a calculation. We will extend these studies to include additional amino acids in KcsA (which, although proton gated, has much in common with voltage gated channels), and will extend the calculations (time permitting) to the voltage sensing domain of voltage gated channels. However, understanding even the relatively simple KcsA channel may provide a key to understanding channel gating more generally, and it is only this channel that we definitely expect to understand by the end of this project. Since there is evidence that all K+ channels at least have a great deal in common, this should provide a good basis for understanding voltage gating as well. Specifically, we will look at the hydrogen bonding network at the extracellular side of the gating region (which is at the intracellular end of the channel); then we will investigate the "bundle crossing" of amino acids further to the extracellular side, which appears to include the pivot on which the gate swings open. If we completely understand these two regions, we should have succeeded in the fundamental aims of the project. We optimize with a relatively small basis set, and use single point calculations with a large basis set for energy calculations (which also check the optimization).
Project Details
Project type
Large-Scale EMSL Research
Start Date
2007-06-14
End Date
2008-06-15
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Kariev AM, and ME Green. 2012. "Voltage Gated Ion Channel Function: Gating, Conduction, and the Role of Water and Protons." International Journal of Molecular Sciences 13(2):1680-1709. doi:10.3390/ijms13021680