ИСТИНА

The calcium-activated potassium channels (KCa channels) are widely expressed in the organism. Several studies demonstrated the potential role of KCa3.1 channel blockage as a therapeutic strategy. Knowledge of the molecular aspects of blockers binding process is an important step in design highly efficient and selective ligands. Goal of the current study was an interface analysis in complexes of hybrid channel KcsA-KCa3.1 with peptide blockers agitoxin, charybdotoxin and maurotoxin. KcsA-KCa3.1 chimera represents KcsA channel with P–loop taken from the human KCa3.1. 3D structure was generated by homology modeling using complex of mutated KcsA channel with charybdotoxin (pdb-code 2A9H) as a template. Molecular dynamic simulation was performed using Gromacs software. Optimal conformations of toxins in channel binding site were chosen from the trajectories. Hydrophobic and stacking interactions, hydrogen and ionic bonds of the toxins and hybrid channel were evaluated using program Platinum and APBS software package. Contacts energy characteristics evaluation showed that maurotoxin was the most effective blocker of KCa3.1 channel among these toxins. This result is in good agreement with the experimental data. Knowledge of channel-toxins interfaces allowed us to propose amino acid mutations in toxins to increase binding affinity and selectivity. Results of the conducted investigation are of great interest for drug development.