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

Abstract

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 modulating the lipid membrane structure. We found that the conformational ensembles adopted by different steroids vary greatly, as quantified by their distributions of tilt angles and insertion depths into the membrane, ranging from well-defined steroid conformations with orientations either parallel or normal to the membrane, to wide conformational distributions. Surprisingly, despite their chemical diversity, the membrane/water partition coefficient is similar among most steroids, except for structural steroids such as cholesterol, leading to similar rates for exiting the membrane. By contrast, the rates of steroid flip–flop vary by at least 9 orders of magnitude, revealing that flip–flop is the rate-limiting step during cellular uptake of polar steroids. This study lays the ground for a quantitative understanding of steroid–membrane interactions, and it will hence be of use for studies of steroid biosynthesis and function as well as for the development and usage of steroids in a pharmacological context.

Molecular dynamics simulations and experimental studies reveal differential permeability of withaferin-A and withanone across the model cell membrane

“…As expected, because of their overall lipophilic nature, these molecules tend to localize below or near the ester groups of POPC at the interface between polar or apolar regions of the membrane. Similar locations for other steroids are reported in literature 72 . The different orientations acquired by Wi-A and Wi-N while passing through the lipid membrane is shown in Supplemetary Figs.…”

“…This particular configuration imposed a specific vertical orientation (i.e. parallel to bilayer normal) position, such that the hydrophobic groups were solvated by the lipid tails and the polar groups (O5 and O4) can form hydrogen bonds with other polar parts of the membrane 72 . In addition to orientation, another major degree of freedom was given by the positions of the withanolides relative to the membrane center of mass, which is the insertion depth in the membrane (Table 2 ).…”

The Membrane Cholesterol Modulates the Interaction Between 17-βEstradiol and the BK Channel

“…17β-Estradiol is a steroid hormone involved in diverse physiological functions, including a protective effect against cardiovascular diseases (CVD) (Gao and Dahlman-Wright, 2011). In order to induce their effects, E2 must cross the plasma membrane to interact with intracellular receptors or bind to membrane steroid receptors and ion channels (Gao and Dahlman-Wright, 2011;Atkovska et al, 2018). In that way, it is relevant to the understanding of estradiolmembrane interactions and how changes in plasma membrane properties can affect this interaction.…”

Approaches to CNS Drug Delivery with a Focus on Transporter-Mediated Transcytosis

“…Additionally, increased polarity and/or lipophilicity may enhance drug binding to serum proteins via H-bonding and lipophilic interactions, respectively, which, in turn, reduces its AUC 0 T , and therefore, C br [25,45]. Molecular flexibility, induced by rotatable bonds, allows the drug molecule to wiggle through the long chains of the membrane lipids [25,46]. However, excessive molecular flexibility may have the opposite effect if the drug molecule can adopt an array of conformations among which are bulky geometries [25,46].…”

“…Molecular flexibility, induced by rotatable bonds, allows the drug molecule to wiggle through the long chains of the membrane lipids [25,46]. However, excessive molecular flexibility may have the opposite effect if the drug molecule can adopt an array of conformations among which are bulky geometries [25,46]. As for molecular volume which is a function of molecular weight and structure including all accessible conformations the drug molecule can adopt under the physiological conditions, the more compact it is the greater is the likelihood of the drug traversing the BBB by passive diffusion through its ECs’ LBL membranes [25].…”