Figure 1.
The Selectivity Filter of the hERG channel.
The SF and the regions of the channel located in proximity of it are displayed as sticks and ribbons. For clarity, only two opposite subunits of the channel are shown. The depicted SF occupancy state (here referred to as S5[S3,S1]) involves three potassium ions and three water molecules (shown as van der Waals spheres). The additional water molecule placed behind the SF is also shown.
Figure 2.
Schematic models of ion permeation.
The ion permeation along a schematic selectivity filter displaying four coordination sites is shown. The cycle involves two opposite configurations of a doubly occupied filter (on the left and on the right), while a third ion is transferred from the intra- to the extra-cellular side. Only the rate limiting step of the whole permeation cycle is shown. The ion translocation can be achieved via both a knock-on (lower pathway) and a vacancy diffusion mechanism (upper pathway).
Figure 3.
The starting configuration for the complete (S1–S6) hERG model immersed in the DOPC lipid bilayer displayed as ribbons and sticks, respectively. For sake of clarity, water molecules and ions employed in the simulations are not shown.
Figure 4.
Energetics of ion conduction through the SF.
Projections of the free energy as a function of S and Z (panel A), and S and NS2,S3 (panel C) are shown as contour plots using an iso-line separation of 1 kcal mol−1. In panel A, the labels corresponding to the main basins found by the simulation (I to VII) as well as a schematic representation of the lowest energy pathways for the vacancy diffusion (pathway 1) and the knock on mechanism (pathway 2) are also shown. The representative configurations of the free energy basins are displayed in B. The arrow in the configuration corresponding to basin IV indicates a typical flipping of the Val625 carbonyl. D, representation of the K+ density of the filter averaged over the metadynamics trajectory.
Figure 5.
Stability of the coordination sites S1 and S4.
Free energy profiles describing the stability of the coordination sites S1 and S4 as a function of NS1 (panel A) and NS4 (panel B), respectively. In both cases, the S5,[S3,S1] occupancy state of the filter was used. In the insets, representative configurations of the filter are shown.
Figure 6.
Effect of negatives charges behind the filter.
A, the SF of the Asn629Asp mutant. B, Free energy of ion conduction as a function of S and Z calculated for the mutant. The free energy surface is shown as contour plot using an iso-line separation of 1 kcal mol−1.