Curcumin Protects Membranes through a Carpet or Insertion Model Depending on Hydration

Abstract

Curcumin is the main ingredient in turmeric, a common Indian spice. Curcumin shows a broad spectrum of effects, including anti-Alzheimer's and antioxidant properties. An interaction between curcumin and lipid membranes has been speculated as the root cause of this activity, and the molecule is often proposed to protect the bilayer. However, the detailed molecular mechanism of this protection is disputed. There is evidence that curcumin either (a) lies flat on the bilayer and provides a "carpet" for protection by forming a steric barrier, or (b) inserts into the membrane and stiffens tails, thereby protecting against peptide insertion. We studied the interaction between curcumin and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) bilayers at different concentrations using high-resolution X-ray diffraction and molecular dynamics (MD) computer simulations. We observed curcumin molecules forming a carpet in dehydrated bilayers, whereas in hydrated membranes the curcumin molecules were found to insert into the bilayers. From calculations of the potential of mean force (PMF), we find two minima, a metastable state in the headgroup region, at |z| ≈ 22 Å, and a global minimum in the hydrophobic membrane core, at |z| ≈ 9 Å. The population of the two states depends on membrane hydration. Experiments may thus observe curcumin in a carpet or inserted position, depending on the osmotic pressure conditions created, for instance, by salts, buffer solutions, substrates, or macromolecular solutes. In the carpet model, curcumin dehydrates lipid bilayers and decreases fluidity. When inserted, curcumin leads to a further fluidification of the membranes and an increase in tail fluctuations, contrary to cholesterol's condensing effect.

Effects of Curcumin on Lipid Membranes: an EPR Spin-label Study

“…The results of 2 H and 14 N NMR measurements obtained by Kotenkov et al [12] showed that curcumin is not embedded deep in the lipid bilayer of multilamellar liposomes and interacts mainly with the lipid headgroups. In the carpet model, according to which curcumin lies flat on the lipid headgroups it dehydrates lipid bilayers and decreases fluidity [11]. In the DMPC/cholesterol mixture addition of curcumin amplifies the effect of cholesterol on the ordering of lipid acyl chains [12].…”

“…By modulating those properties, curcumin may also make membrane less prone to oxidative stress. Because of that, curcumin's way of action was often compared with that of cholesterol [9][10][11][12]. Similar to cholesterol, curcumin was proposed to be anchored to the lipid bilayer near the phosphate group and to stiffen membranes by inducing segmental ordering of lipids [9].…”

“…Some results suggest that curcumin lies flat on the lipid headgroups, where it forms hydrogen bonds with the lipid molecules [25], whereas some other show that curcumin can penetrate deeply into the membrane and intercalate with the lipid tails [6,9]. According to one of the recent papers, both locations are possible depending on membrane hydration [11]. Simulation studies showed that curcumin distribution in the membrane depends on the lipid type [26].…”

“…1). Depending on curcumin location in the membrane, different models of its protective activity are proposed: as a physical barrier, a so-called carpet, preventing peptide or oxidants penetration if associated with the membrane at the surface or by membrane stiffening and increasing the energy barrier to ion or peptide embedding if positioned perpendicular to the membrane surface and penetrating between the alkyl chains of lipids [11].…”

Magnetoliposomes Incorporated in Peptide-Based Hydrogels: Towards Development of Magnetolipogels

“…The strong fluorescence emission of curcumin is an indication of its presence in the lipid membranes, as it is very weakly emissive in water [11,14]. It has also been reported that curcumin inserts into lipid bilayers in a hydrated environment [23]. Further, the same emission maximum in both liposomes and AMLs (503 nm) indicates that nanoparticles do not affect the membranes.…”