Simulation of the Interaction Between ScyTx and Small Conductance Calcium-Activated Potassium Channel by Docking and MM-PBSA

Abstract

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.

Paratope and Epitope Mapping of the Antithrombotic Antibody 6B4 in Complex with Platelet Glycoprotein Ibα

“…GPIb␣, however, is a molecule with several known conformations, and also antibodies rearrange their residue side and/or main chains to improve the affinity for their targets. One way to overcome this problem would be to perform molecular dynamics simulations followed by calculation of relative free binding energies with the molecular mechanics Poisson-Boltzmann surface area as, for example, Wu et al (23) did to resolve the interaction between the scorpion toxin ScyTx and the small conductance calcium-activated potassium channel Rsk2. An alternative strategy, which we followed, is using a docking strategy method that allows flexibility in both ligand (6B4) and target (GPIb␣), such as HADDOCK1.3.…”

Molecular dynamics of nor-Seco-cucurbit[10]uril complexes

“…The free energy DG PB was computed in continuum solvent using the MM-PBSA program of AMBER 11, whereas DG NP was calculated from the solvent-accessible surface area (SASA) [31] according to:…”

A model of BmK CT in inhibiting glioma cell migration via matrix metalloproteinase-2 from experimental and molecular dynamics simulation study

“…expasy.org/) was performed as reported previously (Peitsch 1995;Guex and Peitsch 1997;Schwede et al 2003;Kopp and Schwede 2004;Arnold et al 2006). Protein-protein interactions by docking methods using ZDOCK (a fourier transform-based protein docking program) (http://zdock.bu.edu/) is preferred when high-resolution three dimensional structure of protein complex is not available (Wu et al 2004). The quality of generated binding model is then further optimized by energy minimization and molecular dynamics (MD) simulation using Insight II 2000 software package developed by Accelrys.…”

“…Electrostatic effects play a pivotal role in the interaction between the ion channels and the small basic peptides of the scorpion toxins (Wu et al 2004). In the present study, influence of basic residues in BmK CT on the inhibitory activity to MMP-2 was studied using computational methods and we now propose a model of the structural mechanism that may explain the inhibitory effect of this Cltx-like neurotoxin on glioma migration.…”