Computed energies for an inhibitory sterol (cholesterol) and its inactive diastereomer (epicholesterol) to adopt a planar conformation and, thus, induce membrane deformation during channel opening are similar. (A) Computational model of the cholesterol molecule in its lowest energy (left) and its stable planar conformation (right). The energy associated with the switch from the molecule’s lowest energy to its planar conformation (dE) is expected to lead to increased membrane deformation energy barrier during channel opening. (B) Table displaying cholesterol and epicholesterol lowest (E_min) and planar conformation (E_pl) energies, and dE for each monohydroxysterol. Energies are given in kilocalorie/mole.