Differential molecular interactions between iberiotoxin and human SLO3 and SLO1 potassium channels

SLO1and SLO3 are similar voltage-gated K + channels. However, SLO3 expression is sperm specific and plays an important role in the hyperpolarization of the sperm membrane potential that is crucial for sperm fertilization. This makes SLO3 an excellent molecular target for the development of male contraceptives, and computational methods can facilitate structural insights for this drug development. Here, we evaluated the differential molecular interactions between the human SLO3 (hSLO3) and SLO1 (hSLO1) potassium channels and iberiotoxin (IbTX), a toxin that selectively blocks SLO channels. To do this, molecular docking and dynamics were implemented on the channel-toxin complexes to help elucidate atomistic details of their interaction and binding energy. Our analysis found that IbTX has a similar binding energy to both channels but interacts in a distinct manner with them. Particularly, Trp14 and Arg25 residues of IbTX diverges in their interaction with the residues Val283 and Asn260 residues of hSLO3 and the corresponding residues Tyr359 and Ala336 of hSLO1. Knowledge of key residues in the molecular interface of IbTX blockage can help guide and hasten non-hormonal contraceptive development. Our results encourage the use of toxins as scaffolds for specific SLO3 blockers.

Atomistic molecular dynamics were implemented on the channel-toxin complexes. To generate the complexes, IbTX was docked to the channels using HADDOCK. CHARMM-GUI was used to generate simulation systems. GROMACS v2023.1 was used to run the simulations for 500 ns in an NPT ensemble at 297.26 K employing the CHARMM36 force field. Binding energy was evaluated by molecular mechanics generalized born surface area (MM/GBSA) with gmxMMPBGBSA.py.