Rationalizing Steroid Interactions with Lipid Membranes: Conformations, Partitioning, and Kinetics

Steroids have numerous physiological functions associated with cellular signaling or modulation of the lipid membrane structure and dynamics, and as such, they have found broad pharmacological applications. Steroid–membrane interactions are relevant to multiple steps of steroid biosynthesis and action, as steroids are known to interact with neurotransmitter or membrane steroid receptors, and steroids must cross lipid membranes to exert their physiological functions. Therefore, rationalizing steroid function requires understanding of steroid–membrane interactions. We combined molecular dynamics simulations and isothermal titration calorimetry to characterize the conformations and the energetics of partitioning, in addition to the kinetics of flip–flop transitions and membrane exit, of 26 representative steroid compounds in a model lipid membrane. The steroid classes covered in this study include birth control and anabolic drugs, sex and corticosteroid hormones, neuroactive steroids, as well as steroids mod...