Dataset Information

Integrative Approach for Computationally Inferring Interactions between the Alpha and Beta Subunits of the Calcium-Activated Potassium Channel (BK): a Docking Study.

ABSTRACT: Three-dimensional models of the alpha- and beta-1 subunits of the calcium-activated potassium channel (BK) were predicted by threading modeling. A recursive approach comprising of sequence alignment and model building based on three templates was used to build these models, with the refinement of non-conserved regions carried out using threading techniques. The complex formed by the subunits was studied by means of docking techniques, using 3D models of the two subunits, and an approach based on rigid-body structures. Structural effects of the complex were analyzed with respect to hydrogen-bond interactions and binding-energy calculations. Potential interaction sites of the complex were determined by referencing a study of the difference accessible surface area (DASA) of the protein subunits in the complex.

SUBMITTER: Gonzalez J

PROVIDER: S-EPMC3588595 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Integrative Approach for Computationally Inferring Interactions between the Alpha and Beta Subunits of the Calcium-Activated Potassium Channel (BK): a Docking Study.

González Janneth J Gálvez Angela A Morales Ludis L Barreto George E GE Capani Francisco F Sierra Omar O Torres Yolima Y

Bioinformatics and biology insights 20130227

Three-dimensional models of the alpha- and beta-1 subunits of the calcium-activated potassium channel (BK) were predicted by threading modeling. A recursive approach comprising of sequence alignment and model building based on three templates was used to build these models, with the refinement of non-conserved regions carried out using threading techniques. The complex formed by the subunits was studied by means of docking techniques, using 3D models of the two subunits, and an approach based on ...[more]

PMID: 23492851

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Project description:Computational methods are employed to simulate interaction of scorpion toxin ScyTx in complex with the small conductance calcium-activated potassium channel rsk2. All of available 25 structures of ScyTx in the Protein Data Bank determined by NMR were considered for improving performance of rigid protein docking of ZDOCK. Four main binding modes were found among a large number of predicted complexes by using clustering analysis, screening with expert knowledge, energy minimization, and molecular dynamics simulations. The quality and validity of the resulting complexes were further evaluated by molecular dynamics simulations with the generalized Born solvation model and by calculation of relative binding free energies with the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) in the AMBER 7 suit of programs. The complex formed by the 22nd structure of the ScyTx and rsk2 channel was identified as the most favorable complex by using a combination of computational methods, which contain further introduction of flexibility without restraining residue side chain. From the resulted spatial structure of the ScyTx and rsk2 channel, ScyTx associates the mouth of the rsk2 channel with alpha-helix rather than beta-sheet. Structural analysis first revealed that Arg(13) played a novel and vital role of blocking the pore of the rsk2 channel, whose role is remarkably different from that of highly homologous scorpion toxin P05. Between the interfaces in the ScyTx-rsk2 complex, strong electrostatic interaction and hydrogen bonds exist between Arg(13) of ScyTx and Gly-Tyr-Gly-Asp sequential residues located in the four symmetrical chains of the pore region. Simultaneously, five hydrogen bonds between Arg(6) of ScyTx and Asp(341)(C), Val(366)(C), and Pro(367)(C), and electrostatic interaction between Arg(6) of ScyTx and Asp(364)(B) and Asp(341)(C) are also found by structural analysis. In addition, His(31) located at the C-terminal of ScyTx is surrounded by Val(342)(A), Asp(364)(A), Met(365)(A), Pro(367)(B), and Asn(366)(B) within a contact distance of 4.0 A. These simulation results are in good agreement with experimental data and can effectively explain the binding phenomena between ScyTx and the potassium channel at the level of molecular spatial structure. The consistency between results of molecular modeling and experimental data strongly suggests that our spatial structure model of the ScyTx-rsk2 complex is reasonable. Therefore, molecular docking combined with molecular dynamics simulations followed by molecular mechanics Poisson-Boltzmann surface area analysis is an attractive approach for modeling scorpion toxin-potassium channel complexes a priori for further biological studies.

Dataset Information

Integrative Approach for Computationally Inferring Interactions between the Alpha and Beta Subunits of the Calcium-Activated Potassium Channel (BK): a Docking Study.

Publications

Integrative Approach for Computationally Inferring Interactions between the Alpha and Beta Subunits of the Calcium-Activated Potassium Channel (BK): a Docking Study.

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