Role of terminal dipole charges in aggregation of α-helix pair in the voltage gated K+ channel

Abstract

The voltage sensor domain (VSD) of the potassium ion channel KvAP is comprised of four (S1-S4) α-helix proteins, which are encompassed by several charged residues. Apart from these charges, each peptide α-helix having two inherent equal and opposite terminal dipolar charges behave like a macrodipole. The activity of voltage gated ion channel is electrostatic, where all the charges (charged residues and dipolar terminal charges) interact with each other and with the transmembrane potential. There are evidences that the role of the charged residues dominate the stabilization of the conformation and the gating process of the ion channel, but the role of the terminal dipolar charges are never considered in such analysis. Here, using electrostatic theory, we have studied the role of the dipolar terminal charges in aggregation of the S3b-S4 helix pair of KvAP in the absence of any external field (V=0). A system attains stability, when its potential energy reaches minimum values. We have shown that the presence of terminal dipole charges (1) change the total potential energy of the charges on S3b-S4, affecting the stabilization of the α-helix pair within the bilayer lipid membrane and (2) the C- and the N-termini of the α-helices favor a different dielectric medium for enhanced stability. Thus, the dipolar terminal charges play a significant role in the aggregation of the two neighboring α-helices.

Spin dynamics in helical molecules with nonlinear interactions

“…In an α-helix, the peptide dipoles are aligned in such a way that about 97% of the peptide dipole moments point in the direction of the helix axis [35] (see figure 1(a)). Therefore, α-helices can be regarded as macrodipoles, having a total dipole moment of the order of 3.5N Debye (N is the number of residues), pointing from the negative C-terminus to the positive N-terminus of the helix (see [36] and references therein). The magnitude of the electric dipole of the molecule is not a fixed value but depends on the molecular conformation and on its local environment.…”

Effect of dielectric interface on charge aggregation in the voltage-gated K+ion channel

“…There is no hard evidence for this assumption except that S3b and S4 are stuck together in all available crystal structures, and our theoretical study has also shown that there is a strong electrostatic interaction between them. [ 8 ] But the exposure of the extracellular and intracellular end of the S3b and S4 helices can be different, due to the flexibility of the paddle and deep water-filled crevices, which have been found by electron paramagnetic resonance (EPR) spectroscopy of an isolated VSD of KvAP. [ 17 ] S3b being in the interior, all the charges (+N3, −C3, -E107 and +H109) are embedded in protein, while on the periphery of the ion channel, S4 α-helix is assumed to be half exposed to the protein and the other half to the dielectric medium of the environment on the helix side.…”

“…This is consistent with our previous report on the role of dipolar terminal charges, which explained that the dipole charges exposed to lipid lowers the PE and these positive and negative half electronic charges on either end of a α-helix are not insignificant. [ 8 ]…”

“…(3) for any type of ion channel with ampiphilic α-helices. Using this program we have shown previously[ 7 8 ] that apart from the positive charged arginines of the S4 α-helix, the terminal dipole charges have considerable role and the negative charged residue Glutamic acid of S3b α-helix has a dominant role in the aggregation of the S3b-S4 α-helix pair as a paddle. The overall protein shape is considered irregular due to the mobility of the α-helices conforming to variable configuration in hybrid dielectric environment.…”

“…The electrostatic basis of interaction between charges present on the surface or interior of the protein affects its structure and function. Proteins with α-helix secondary structure possess inherent extracellular and intracellular terminal dipole charges,[ 6 ] which interact, with the charged amino-acids[ 7 ] and with the multi-dielectric environment[ 8 ] to affect the minimum energy and bring stability to the system of charges of S3b-S4 helix pair of the voltage sensor domain (VSD) of voltage-gated K + ion channel. The accommodation of the protein and its changing conformation in the lipid membrane is crucial to many biological processes, e.g., gating of ion channels and signal transduction.…”