Elucidation of interaction mechanism of hERG1 potassium channel with scorpion toxins BeKm-1 and BmTx3b.

The human ether-a-go-go related gene 1 (hERG1) K+ channels play crucial role in the heart, different regions of brain, endocrine cells, smooth muscle cells, and numerous tumor cells. It is known that the inherited mutations of hERG1 gene may lead to the disorder of cardiac repolarization (i.e., long QT syndrome (LQTS)), which may result in sudden cardiac death. It is known that K+ ion channels involved in signaling pathways lead to cell proliferation or apoptosis and some specific toxins were investigated for diverse therapeutic applications on targeting the hERG1 K+ channel. Thus, investigation of channel/toxin interactions mechanisms in atomic level is an important topic for the development of toxin-based therapeutics. Thus, in this work, the interaction mechanisms of two toxins named as BeKm-1 and BmTx3b with the closed-state hERG1 channel have been studied by using different molecular modeling techniques including protein-protein docking and molecular dynamics (MD) simulations. The crucial residues of toxins in channel interactions have been elucidated. It is found that R1, K6, K18, R20, K23 and R27 residues in BeKm-1 and F1, K7, K19, K20 and K28 in BmTx3b are the important residues involved in the strong interactions with the closed-state hERG1 K+ channel. The results of this study can be used by medicinal chemists in the designing of diverse therapeutic applications of natural or synthetic peptides targeting the closed state hERG1 K+ channels.