Predicting arrhythmogenicity: structural modeling of safe and unsafe hERG blockers using Rosetta

Human Ether-a-go-go-Related Gene (hERG) encodes a potassium-selective voltage-gated ion channel, KV11.1, essential for normal electrical activity in the heart. hERG mutations and blockage of the channel pore by drugs can cause long QT syndrome (LQTS) that predisposes individuals to arrhythmia and puts them at risk for stroke or sudden cardiac arrest. A major problem in antiarrhythmic drug therapies as well as drug development in general is the proclivity for many drugs and drug candidates to promote fatal arrhythmias through hERG blockade. However, not all hERG blocking drugs are pro-arrhythmic, and their differential affinities to discrete channel states and/or their state stability modulations have been suggested to contribute to arrhythmogenicity. In this study, we used Rosetta electron density refinement, loop rebuilding and homology modeling approaches to build complete structural models of wild-type and mutant hERG channels in open and closed states based on cryo-electron microscopy structures of hERG (pdb id: 5VA2) and the homologous EAG1 channel(pdb id: 5K7L), respectively. Here we present RosettaLigand molecular docking results for drug interactions with hERG in open and closed states. We observed that drugs with different pro-arrhythmia risks like dofetilide and nifekalant have distinct binding poses and affinities in closed and open hERG cavities, which might affect channel gating. Also, Tyr652 residue in hERG pore-lining S6 helix was found to be crucial for stabilizing drug - channel binding in agreement with experiment. Our results provide structural insights into molecular mechanisms of state-dependent drug interactions with hERG that play a key role in differentiating safe and unsafe hERG blockers.