Enantiomers of phospholipids and cholesterol: A key to decipher lipid‐lipid interplay in membrane

Abstract

Most phospholipids constituting biological membranes are chiral molecules with a hydrophilic head group and hydrophobic alkyl chains, rendering biphasic property characteristic of membrane lipids. Some lipids assemble into small domains via chirality‐dependent homophilic and heterophilic interactions, the latter of which sometimes include cholesterol to form lipid rafts and other microdomains. On the other hand, lipid mediators and hormones derived from chiral lipids are recognized by specific membrane or nuclear receptors to induce downstream signaling. It is crucial to clarify the physicochemical properties of the lipid self‐assembly for the study of the functions and behavior of biological membranes, which often become elusive due to effects of membrane proteins and other biological events. Three major lipids with different skeletal structures were discussed: sphingolipids including ceramides, phosphoglycerolipids, and cholesterol. The physicochemical properties of membranes and physiological functions of lipid enantiomers and diastereomers were described in comparison to natural lipids. When each enantiomer formed a self‐assembly or interacted with achiral lipids, both lipid enantiomers exhibited identical membrane physicochemical properties, while when the enantiomer interacted with chiral lipids or with the opposite enantiomer, mixed membranes exhibited different properties. For example, racemic membranes comprising native sphingomyelin and its antipode exhibited phase segregation due to their strong homophilic interactions. Therefore, lipid enantiomers and diastereomers can be good probes to investigate stereospecific lipid‐lipid and lipid‐protein interactions occurring in biological membranes.

Asynchronous Reciprocal Coupling of Martini 2.2 Coarse-Grained and CHARMM36 All-Atom Simulations in an Automated Multiscale Framework

“…Changes in the stereochemistry of lipids can affect their physicochemical properties. − Furthermore, the chirality of peptides can affect their interactions with chiral lipids, and cholesterol chirality can affect membrane protein function . Previous experiment reveals that vesicles composed of 1-palmitoyl-2-elaidoyl- sn -glycero-3-phosphocholine (Δ9- trans POPC) are less susceptible to leakage than POPC vesicles .…”

Sphingomyelins and ent-Sphingomyelins Form Homophilic Nano-Subdomains within Liquid Ordered Domains

“…Therefore, we prepared ent -SSM, an enantiomer of SSM, to evaluate the stereospecific lipid-lipid interactions of SM. Stereochemistry of sphingolipids is reported to have very interesting biological roles ( 15 , 32 , 50 ). Synthetic stereoisomers of lactosylceramides, which share the same ceramide structure with SM, prevent host cells from infection of SV40 virus by inhibiting caveolar endocytosis and the clustering of lipids into “microdomains” ( 50 ).…”

“…Therefore, we have previously investigated the lipid-lipid interactions responsible for nanodomain formation of SM ( 7 , 10 , 11 , 12 ). In general, biophysical approaches using SM-based bilayers have led to a better understanding of the molecular basis of domain formation in biological membranes ( 13 , 14 , 15 ). In particular, the nanoscopic domains and lipid clusters occurring in the Lo phase of model bilayers have recently been examined from physicochemical approaches ( 10 , 12 , 16 , 17 ).…”

Probing the Role of Chirality in Phospholipid Membranes

“…Membranes with SPM and ent-chol compressed more than nat-chol, showing internal membrane enantioselectivity. [39][40][41] Alternatively, this same effect was not seen with cholesterol and DPPC membrane lipids. Interestingly, when a similar experiment compared the interactions of nat-and ent-chol in bilayers containing SPM, rather than monolayers, no enantiospecific effects were observed.…”