Resveratrol induces chain interdigitation in DPPC cell membrane model systems

Resveratrol is a natural polyphenol found in various plants with potential therapeutic activity as anti-oxidant, anti-inflammatory, cardioprotective and anti-tumoral. Lipid membranes are among cellularcomponents that are targets of its action. In this work ESR of chain labeled lipids, calorimetry, X-raydiffraction and molecular docking are used to study the interaction of resveratrol with membrane modelsystems of dipalmitoylphosphatidylcholine (DPPC) as a function of resveratrol concentration (0–30 mol%of the lipid) and temperature (10–50◦C). Resveratrol incorporated in DPPC bilayers induces considerablemotional restriction at the lipid tail termini, removing the gradient of increasing mobility along the chainfound in DPPC bilayers in the gel phase. In contrast, it leaves unperturbed the DPPC chain flexibilityprofile in the liquid-crystalline phase. At low concentration, resveratrol progressively reduces the pre-transition temperature and eliminates the pre-transition for content ≥5 mol%. A reduced cooperativityand a downshift of the main transition temperature are observed, especially at high content. The typicaldiffraction pattern of DPPC multibilayers in the Lphase is converted to a lamellar pattern with reducedd-spacing of untilted lipid chain in a hexagonal packing at 30 mol% of resveratrol. Molecular dockingindicates that the energetically favoured anchoring site is the polar headgroup region, where resveratrolacts as a spacer. The overall results are consistent with the formation in DPPC of an interdigitated Ligelphase induced by 30 mol% resveratrol.