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Abstract
Relaxation of a hERG K+ channel model during molecular-dynamics simulation in a hydrated POPC bilayer was accompanied by transitions of an arginine gating charge across a charge transfer center in two voltage sensor domains. Inspection of the passage of arginine side chains across the charge transfer center suggests that the unique hydration properties of the arginine guanidine cation facilitates charge transfer during voltage sensor responses to changes in membrane potential, and underlies the preference of Arg over Lys as a mobile charge carrier in voltage-sensitive ion channels.
Highlights
This transition is facilitated by changes in side-chain rotamers of R534 and F463 as the planar Arg guanidine group rotates past the F463 ring, and the availability of D460 as a counterion for the R534 guanidine (Fig. 2)
The passage of Gdmþ through the charge-transfer center (CTC) is facilitated by the hydrophobic nature of Gdmþ above and below the molecular plane [13], which allows interaction with the nonpolar groups in the CTC (Fig. 3 A and see Fig. S3)
This contrasts with the solvation properties of the Lys amino group (e.g., K302 of the Kv1.2/2.1 chimera (Fig. 1), which has a spherical distribution of H-bonding and charge-neutralizing oxygen atoms (Fig. 3 D and see Fig. S4)
Summary
In hERG, F463 can be replaced by M, L, or V with small effects on channel gating [17], indicating that the hERG CTC requires only a bulky nonpolar side chain to seal the hydrophobic center of the VS and allow passage of the Arg side chain through the CTC Both absence of requirement for cation-p interactions, and accommodation of nonplanar hydrophobic side chains in a functional hERG CTC, are broadly consistent with the interpretation that it is the poorly-hydrated nature of the Arg guanidine group above and below the molecular plane (together with its tenacious proton affinity [18]) that governs its role in carrying gating charge in voltage sensors.
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