Abstract
Although extensively studied, it has proved difficult to describe in detail how potassium ion channels conduct cations and water. We present a computational study that, by using stratified umbrella sampling, examines nearly an entire conduction event of the Kv1.2/2.1 paddle chimera and thereby identifies the expected stable configurations of ions and waters in the selectivity filter of the channel. We describe in detail the motions of the ions and waters during a conduction event, focusing on how waters and ions enter the filter, the rotation of water molecules inside the filter, and how potassium ions are coordinated as they move from a water to a protein environment. Finally, we analyze the small conformational changes undergone by the protein, showing that the stable configurations are most similar to the experimental crystal structure.
Highlights
Ion channels are proteins that control the flow of ions across polarized cell membranes
Long et al.[2] elucidated the structure of the tetrameric Kv1.2/ 2.1 paddle chimera (Kvchim - Figure 1A), which is functionally similar to Shaker, the canonical voltage-gated potassium ion channel.[3]
How can we examine the conduction of potassium ions by Kvchim in atomistic detail? This is difficult to do by experiment alone because the process of conduction is fast and occurs in a confined, highly optimized space that is very sensitive to perturbation[8] and there is no experimental technique with the sufficient spatial and temporal resolution to resolve a single selectivity filter
Summary
Dynamics simulations have been used to study different aspects of the behavior of potassium ion channels, including how potassium ions and water move through the selectivity filter.[9]. We have calculated a 2D PMF characterizing nearly an entire conduction event through the selectivity filter of the Kv1.2/2.1 chimeric voltage-gated channel, assuming the KwK mechanism is correct This identifies the expected stable configurations of the selectivity filter (wwKwK(K), wKwKw-. We have described in detail the motions of the ions and waters during two ‘knock-on’ events, have shown how the filter is able to smooth the transition of a potassium ion from water into the narrow constriction of the selectivity filter, and have investigated the small conformational changes that occur during a conduction event This is the first study to combine in this fashion the calculation of PMFs with detailed structural analysis. This material is available free of charge via the Internet at http://pubs.acs.org
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