Modeling and Molecular dynamic simulations of a scorpion potent potassium channel blocker: aid in drug development

Modeling and Molecular dynamic simulations of a scorpion potent potassium channel blocker: aid in drug development
Masoumeh Baradaran,^1,*
1. Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
Introduction: Scorpion venom is an important source for biologically active components that can modulate the ion channels (K+, Na+, Cl-, Ca2+) of the human cells. This concept of scorpion-derived peptides could be used to develop new specific drugs. Potassium channels blockers(KTxs), one group of scorpion venom toxins, can be good candidate for treatment of different disease, ranging from asthma, diabetes, angina, cardiac ischemia and hypertension to chronic inflammation, autoimmune disease and cancers. Transcriptome analysis techniques revealed some peptides in the venom gland of Iranian Mesobuthus eupeus, including many toxins. One of them named meuK5_1 that submitted in data bank in certain accession number (KU253402).
Methods: Homology modeling was performed with the program MODELLER for calculation of the 3-D model of meuK5_1. To optimize the obtained homology models molecular dynamic simulation was applied. Molecular dynamic simulation was done with the help of NAMD 2.9 and a time step of 2 fs for 20 ns (10 million steps). CHARMM 27 was utilized to parameterize. VMD software was employed to visualize the trajectories and their analyses, to wit: RMSD and RMSF, radius of gyration and solvent accessible surface area (SASA). Functional similarity of peptides of the same family was used to explain the function of meuK5_1 in which the amino acid residues that could be involved in the potassium channel/toxin interactions was proposed.
Results: The cDNA sequence of meuK5_1 consists of 262 nucleotides that encodes for a precursor with 16AA signal peptide and 42AA mature peptide in length. Refined 3-D structure of meuK5-1 consists of a conserved CSα/β (cysteine-stabilized α-helical and β-sheet) in which a single α-helix connected to a double stranded β-sheet through three disulfide bonds. The connectivity pattern of disulfide bridges is: Cys15-Cys33, Cys19-Cys28, and Cys23-Cys40. functional analysis suggests a key role for residues Lys32 and Tyr41 of meuK5-1 as a “functional dyad” in the interaction and blockage of the potassium channels. According to the current view, Tyr41 interacts with a cluster of ion channel aromatic residues. Then, the side-chain of the Lys32 residue positions itself into the channel pore and interacts with selectivity filter of the channel and thus blocks it.
Conclusion: The information obtained here can be utilized to direct more exploration for better understanding of meuK5-1 to develop a potent pharmaceutical.
Keywords: scorpion toxins, Mesobuthus eupeus, drug development, modeling, molecular dynamic simulation