Insight into the Mechanism of Inactivation and pH Sensitivity in Potassium Channels from Molecular Dynamics Simulations

Abstract

Potassium (K (+)) channels can regulate ionic conduction through their pore by a mechanism, involving the selectivity filter, known as C-type inactivation. This process is rapid in the hERG K (+) channel and is fundamental to its physiological role. Although mutations within hERG are known to remove this process, a structural basis for the inactivation mechanism has yet to be characterized. Using MD simulations based on homology modeling, we observe that the carbonyl of the filter aromatic, Phe627, forming the S 0 K (+) binding site, swiftly rotates away from the conduction axis in the wild-type channel. In contrast, in well-characterized non-inactivating mutant channels, this conformational change occurs less frequently. In the non-inactivating channels, interactions with a water molecule located behind the selectivity filter are critical to the enhanced stability of the conducting state. We observe comparable conformational changes in the acid sensitive TASK-1 channel and propose a common mechanism in these channels for regulating efflux of K (+) ions through the selectivity filter.

An Extracellular Ion Pathway Plays a Central Role in the Cooperative Gating of a K2P K+ Channel by Extracellular pH*

“…1D, which plots the position of the K ϩ ion sited at S0 at the beginning of separate 8-ns MD runs as a function of time. A previous MD study using a TASK-1 homology model proposed that a water molecule located behind the selectivity filter is critical for the stability of the SF, which is disrupted upon His-98 protonation (26). This water molecule is not present in the resolved K 2P structures and was not essential for the conformational changes described here.…”

“…The same authors show that site-directed mutagenesis affecting ion selectivity produced concomitant changes in pH o dependence, consistent with SF gating. Later MD studies provide the important observation that protonation of His-98 leads to a flipping upwards of the sensing His-98, which, in addition to producing a deformation of the SF moving away K ϩ -coordinating backbone carbonyl groups from its lumen, would create "an electropositive barrier to K ϩ ions at the outer mouth of the channel" (26). This proposal is interesting as it links pH o gating with its known K ϩ dependence.…”

“…The homology model was embedded into a pre-equilibrated phosphatidyl oleoyl phosphatidylcholine bilayer in a periodic boundary condition box (10.2 ϫ 10 ϫ 10.5 nm) with pre-equilibrated TIP3P water molecules (27). Three K ϩ ions were associated to the models in positions S0, S2, and S4 of the selectivity filter and two water molecules at sites S1 and S3, respectively (26). Fifty-eight potassium ions were added to the aqueous phase to simulate a concentration of 150 mM K ϩ .…”

Acid-sensitive TWIK and TASK Two-pore Domain Potassium Channels Change Ion Selectivity and Become Permeable to Sodium in Extracellular Acidification

“…How does protonation in the pH o -sensing histidine change ion selectivity of acid-sensitive TWIK and TASK K ϩ channels? A previous study with molecular dynamics simulations predicts that protonation of the pH o -sensing His-98 residue of TASK-1 K ϩ channels induces rotation of the Tyr-96 and Gly-97 peptide, and then the conformation of the selectivity filter changes (25). Voltage-gated Kv2.1 channels change ion selectivity during C-type inactivation (37).…”

“…1C). Protonation of the pH o -sensing histidine is likely to have an impact on the conformation of the selectivity filter (25). Our previous work suggests that the reversal potential of TWIK-1 K ϩ channels may move in the depolarizing direction in lowered pH o (26).…”