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Binding modes of two scorpion toxins to the voltage-gated potassium channel kv1.3 revealed from molecular dynamics.

ABSTRACT: Molecular dynamics (MD) simulations are used to examine the binding modes of two scorpion toxins, margatoxin (MgTx) and hongotoxin (HgTx), to the voltage gated K+ channel, Kv1.3. Using steered MD simulations, we insert either Lys28 or Lys35 of the toxins into the selectivity filter of the channel. The MgTx-Kv1.3 complex is stable when the side chain of Lys35 from the toxin occludes the channel filter, suggesting that Lys35 is the pore-blocking residue for Kv1.3. In this complex, Lys28 of the toxin forms one additional salt bridge with Asp449 just outside the filter of the channel. On the other hand, HgTx forms a stable complex with Kv1.3 when the side chain of Lys28 but not Lys35 protrudes into the filter of the channel. A survey of all the possible favorable binding modes of HgTx-Kv1.3 is carried out by rotating the toxin at 3° intervals around the channel axis while the position of HgTx-Lys28 relative to the filter is maintained. We identify two possible favorable binding modes: HgTx-Arg24 can interact with either Asp433 or Glu420 on the vestibular wall of the channel. The dissociation constants calculated from the two binding modes of HgTx-Kv1.3 differ by approximately 20 fold, suggesting that the two modes are of similar energetics.

SUBMITTER: Chen R

PROVIDER: S-EPMC4113748 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Binding modes of two scorpion toxins to the voltage-gated potassium channel kv1.3 revealed from molecular dynamics.

Chen Rong R Chung Shin-Ho SH

Toxins 20140722 7

Molecular dynamics (MD) simulations are used to examine the binding modes of two scorpion toxins, margatoxin (MgTx) and hongotoxin (HgTx), to the voltage gated K+ channel, Kv1.3. Using steered MD simulations, we insert either Lys28 or Lys35 of the toxins into the selectivity filter of the channel. The MgTx-Kv1.3 complex is stable when the side chain of Lys35 from the toxin occludes the channel filter, suggesting that Lys35 is the pore-blocking residue for Kv1.3. In this complex, Lys28 of the tox ...[more]

PMID: 25054783

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Project description:Based on a homology model of the Kv1.3 potassium channel, the recognitions of the six scorpion toxins, viz. agitoxin2, charybdotoxin, kaliotoxin, margatoxin, noxiustoxin, and Pandinus toxin, to the human Kv1.3 potassium channel have been investigated by using an approach of the Brownian dynamics (BD) simulation integrating molecular dynamics (MD) simulation. Reasonable three-dimensional structures of the toxin-channel complexes have been obtained employing BD simulations and triplet contact analyses. All of the available structures of the six scorpion toxins in the Research Collaboratory for Structural Bioinformatics Protein Data Bank determined by NMR were considered during the simulation, which indicated that the conformations of the toxin significantly affect both the molecular recognition and binding energy between the two proteins. BD simulations predicted that all the six scorpion toxins in this study use their beta-sheets to bind to the extracellular entryway of the Kv1.3 channel, which is in line with the primary clues from the electrostatic interaction calculations and mutagenesis results. Additionally, the electrostatic interaction energies between the toxins and Kv1.3 channel correlate well with the binding affinities (-logK(d)s), R(2) = 0.603, suggesting that the electrostatic interaction is a dominant component for toxin-channel binding specificity. Most importantly, recognition residues and interaction contacts for the binding were identified. Lys-27 or Lys-28, residues Arg-24 or Arg-25 in the separate six toxins, and residues Tyr-400, Asp-402, His-404, Asp-386, and Gly-380 in each subunit of the Kv1.3 potassium channel, are the key residues for the toxin-channel recognitions. This is in agreement with the mutation results. MD simulations lasting 5 ns for the individual proteins and the toxin-channel complexes in a solvated lipid bilayer environment confirmed that the toxins are flexible and the channel is not flexible in the binding. The consistency between the results of the simulations and the experimental data indicated that our three-dimensional models of the toxin-channel complex are reasonable and can be used as a guide for future biological studies, such as the rational design of the blocking agents of the Kv1.3 channel and mutagenesis in both toxins and the Kv1.3 channel. Moreover, the simulation result demonstrates that the electrostatic interaction energies combined with the distribution frequencies from BD simulations might be used as criteria in ranking the binding configuration of a scorpion toxin to the Kv1.3 channel.

Dataset Information

Binding modes of two scorpion toxins to the voltage-gated potassium channel kv1.3 revealed from molecular dynamics.

Publications

Binding modes of two scorpion toxins to the voltage-gated potassium channel kv1.3 revealed from molecular dynamics.

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