The interaction of steroids with phospholipid bilayers and membranes

Abstract

Steroids are critical for various physiological processes and used to treat inflammatory conditions. Steroids act by two distinct pathways. The genomic pathway is initiated by the steroid binding to nuclear receptors while the non-genomic pathway involves plasma membrane receptors. It has been proposed that steroids might also act in a more indirect mechanism by altering biophysical properties of membranes. Yet, little is known about the effect of steroids on membranes, and steroid-membrane interactions are complex and challenging to characterise. The focus of this review is to outline what is currently known about the interactions of steroids with phospholipid bilayers and illustrate the complexity of these systems using cortisone and progesterone as the main examples. The combined findings from current work demonstrate that the hydrophobicity and planarity of the steroid core does not provide a consensus for steroid-membrane interactions. Even small differences in the substituents on the steroid core can result in significant changes in steroid-membrane interactions. Furthermore, steroid-induced changes in phospholipid bilayer properties are often dependent on steroid concentration and lipid composition. This complexity means that currently there is insufficient information to establish a reliable structure-activity relationship to describe the effect of steroids on membrane properties. Future work should address the challenge of connecting the findings from studying the effect of steroids on phospholipid bilayers to cell membranes. Insights from steroid-membrane interactions will benefit our understanding of normal physiology and assist drug development.

Keywords: Cortisone; Membranes; Molecular interactions; Non-genomic effect; Phospholipid bilayers; Progesterone; Steroids.

Fig. 1

Direct and indirect mechanism of steroids associated with their non-genomic pathways. Direct interaction involves the steroid binding to a receptor in the plasma cell membrane. Depending on the location of the receptor binding site, this mechanism may or may not involve interactions with the phospholipid bilayer part of the membrane. The indirect mechanism involves the steroid binding to the phospholipid bilayer and, at sufficiently high concentration, altering the structure or fluidity of the membrane, which subsequently affects the receptor

Fig. 2

Structure and nomenclature of steroids. The rings in the steroid core are denoted by A, B, C and D and the carbons numbered 1 to 17

Fig. 3

Effect of cortisone on the structure of POPC bilayers as determined by X-ray diffraction experiments and molecular dynamics simulations in a study by (Alsop et al. 2016). A Electron density profiles from MD simulations of POPC bilayers with increasing concentrations of cortisone. z(Å) refers to the bilayer normal where z = 0 is the centre of the bilayer (where the POPC lipid tails meet). B, C Area per lipid (B) and lipid order parameter (C) as a function of cortisone concentrations obtained from MD simulations of a POPC bilayer in the presence of increasing cortisone concentrations. D X-ray diffraction pattern of POPC membranes containing increasing amounts of cortisone. E Lamellar spacing (d_z) and membrane thickness (d_HH) of stacked POPC membranes. F d_z and d_HH of POPC bilayers as a function of cortisone concentrations. A–D and F adapted from (Alsop et al. 2016)

Fig. 4

Effect of cortisone on the structure of POPC-cholesterol (7:3 mol%) bilayers as determined by X-ray diffraction experiments and molecular dynamics simulations by (Khondker et al. 2019). X-ray diffraction pattern (A) and d_z and d_HH (B) of POPC-chol membranes containing increasing amounts of cortisone. Figures adapted from (Khondker et al. 2019)

Fig. 5

Insertion depth and orientation of a steroid molecule in the membrane. Insertion depth is usually defined by distances between the steroid and the membrane COM or the phosphate groups. If the resolution of the method allows it, insertion depth of the steroid head and tail can be defined separately. Orientation is defined by the angle formed between vectors running along the steroid and the membrane normal

Fig. 6

Orientation of pregnenolone and progesterone in POPC bilayers obtained from MD simulations by Atkovska et al. (2018). a, d Structure of pregnenolone and progesterone. b, e Snapshots from simulations. Head groups are shown as ball and stick representation, lipid tails as grey lines and pregnenolone and progesterone as sticks in cyan/red (hydrogen atoms not shown). c, f Density vs cos (α) showing the distribution of orientations of pregnenolone and progesterone in POPC bilayer. The tilt angle α is defined as the angle formed between vectors running along the steroid and the membrane normal (see Fig. 5). Figures adapted from Atkovska et al. (2018)

Fig. 7

Structure of progesterone derivatives studied by Abboud et al. (2015)

Fig. 8

Temperature-dependent phase changes in phospholipid bilayers

Fig. 9

Structure–activity relationship studies on the propensity of steroids to promote or disrupt lipid domains by (Wenz and Barrantes 2003). a Structure of sterols and steroids investigated. The isooctyl side chains in the lipid domain-promoting steroids are circled. b Diagram illustrating the principle of quenching in membranes composed of saturated and unsaturated phospholipid, the fluorescent quenching lipid 12-SLPC and the fluorescent probe DPH. c Domain formation stabilisation coefficient (DSCF) for 11 sterols/steroids calculated based on fluorescence quenching and polarisation measurements. Positive and negative values indicate domain-promoting and domain-disrupting activity, respectively. Inset: scatterplot of DSCF from polarisation vs DSCF from quenching. Reprinted with permission from Wenz and Barrantes, Biochemistry, 2003. Copyright 2003 American Chemical Society

Fig. 10

Structure of steroids and sterols studied by Wang et al. (Wang et al. 2004) for their ability to form and stabilise ordered lipid domains. Reprinted with permission from Wang et al., Biochemistry, 2004. Copyright 2004 American Chemical Society