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. 2010 Apr;78(5):1105-19.
doi: 10.1002/prot.22632.

Cooperative nature of gating transitions in K(+) channels as seen from dynamic importance sampling calculations

Elizabeth J Denning  1 , Thomas B Woolf
Affiliations

Cooperative nature of gating transitions in K(+) channels as seen from dynamic importance sampling calculations

Elizabeth J Denning et al. Proteins. 2010 Apr.

Abstract

The growing dataset of K(+) channel x-ray structures provides an excellent opportunity to begin a detailed molecular understanding of voltage-dependent gating. These structures, while differing in sequence, represent either a stable open or closed state. However, an understanding of the molecular details of gating will require models for the transitions and experimentally testable predictions for the gating transition. To explore these ideas, we apply dynamic importance sampling to a set of homology models for the molecular conformations of K(+) channels for four different sets of sequences and eight different states. In our results, we highlight the importance of particular residues upstream from the Pro-Val-Pro (PVP) region to the gating transition. This supports growing evidence that the PVP region is important for influencing the flexibility of the S6 helix and thus the opening of the gating domain. The results further suggest how gating on the molecular level depends on intra-subunit motions to influence the cooperative behavior of all four subunits of the K(+) channel. We hypothesize that the gating process occurs in steps: first sidechain movement, then inter-S5-S6 subunit motions, and lastly the large-scale domain rearrangements.

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Figures

Figure 1
Figure 1
Sequences and structure of the pore domain. (A) An alignment of the four different K+ channel pore-domain sequences. (B) Cartoon of two different configurations of the K+ pore domain representing the closed state transition to the open state. Black and yellow lines outline representations of the implicit bilayer (hydrophobic core and interface regions).
Figure 2
Figure 2
The average angle of the S6 domain relative to the z-axis as a function of RMS, the DIMS progress variable. The errorbars indicate the standard deviation at a particular RMS value. Both transition path directions are shown. (A) KcsA (B) KvAP (C) Kv1.2 (D) MthK.
Figure 3
Figure 3
The S6 kink angle located near the PVP region as a function of RMS (A) KcsA sequence closed to open transitions (B) KvAP sequence closed to open transitions (C) Kv1.2 sequence closed to open transitions (D) MthK sequence closed to open transitions (E) KcsA sequence open to closed transitions (F) KvAP sequence open to closed transitions (G) Kv1.2 sequence open to closed transitions (H) MthK sequence open to closed transitions
Figure 4
Figure 4
The pore domain radius value as function of ΔRMSD (in the closed → open direction) and z-position for the trajectories. The contour color-bar indicates the pore radius value in Ångstroms. (A) Sideview of pore domain depicting basic HOLE profile (B) KcsA transitions (C) KvAP transitions (D) Kv1.2 transitions (E) MthK transitions
Figure 5
Figure 5
Correlations between S5 and S6 movement for all subunits as the pore domain changes conformation observed within the same subunit and with adjacent subunits. Left to right: closed state (−ΔRMSD) to open state (+ΔRMSD). (A) Top down view indicating the location of subunit numbers (B) KcsA transitions (C) KvAP transitions (D) Kv1.2 transitions (E) MthK transitions
Figure 6
Figure 6
Characterization of behavior for hydrophobic residues important to the gating process. Each shape represents a different segment number of the channel (square = segment 1, diamond = segment 2, triangle = segment 3, circle = segment 4).
Figure 7
Figure 7
WT and F103A mutant cumulative Onsager-Machlup (OM) scores. The rank ordering of the trajectories shows the diversity of the transitions for each sequence in the closed → open direction. The solid line represents the WT transition and the dashed-line represent the mutant transition. (A) KcsA transitions, (B) KvAP transitions, (C) Kv12 transitions, (D) MthK transitions.
Figure 8
Figure 8
Motions encoded within different structures using the percent overlap of the displacement vector for the pore domain as a function of mode. Each line represents a different displacement vector (KcsaA → Kv1.2, KcsaA (1k4c) → MthK, KcsA (3eff) → MthK, and Kv1.2 → KcsA). Note: the KcsA → X (X = MthK, Kv1.2) displacement vectors were analyzing transitions generated between the KcsA (1k4c) and MthK (1lnq) endpoints and the Kv1.2 → KcsA displacement vector was analyzing for transitions generated between the KcsA (1k4c) and Kv1.2 (2a79) endpoints.
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