The voltage-gated potassium channel, KV11.1, encoded by the human ether-a-go-go related gene (hERG) is expressed in cardiac myocytes, where it is crucial for the membrane repolarization of the action potential. hERG is implicated in a number of drug-induced arrhythmias, caused by long QT syndrome. Gating of hERG is characterized by rapid, voltage-dependent, C-type inactivation, which blocks ion conduction and is suggested to involve constriction of the selectivity filter. To explore conformational changes associated with hERG inactivation, we use RosettaRelax to simulate the effects of hERG mutations. We show that a lateral shift of residue F627 in the selectivity filter into the central channel axis along the ion conduction pathway. Non-inactivating mutations S620T and S641T showed a potential blocking mechanism of F627 rearrangement, preventing it from shifting into the conduction pathway during the proposed inactivation process. Furthermore, drug docking results correlate well with existing experimental evidence of protein-ligand contacts between high-affinity hERG blockers and key residues Y652 and F656 inside the pore cavity, in addition to illuminating potentially new ligand binding interactions in the inactivated state fenestration region.