Dimeric Polyphenol Effect on Liquid-Ordered and Liquid-Disordered Membranes: Combined Insights from Molecular...

Dimeric polyphenols have been postulated to be more effective in preventing obesity than monomeric ones; however, the mechanism through which polyphenols act on cells remains poorly understood. A leading hypothesis is the inactivation of the intracellular lipid synthesis signaling pathway that leads to lipid accumulation in 3T3-L1 preadipocytes through interference with the signaling activity of the raft domains of their plasma membranes. Thus, understanding the behavior of polyphenols on the membrane surface is essential to elucidating the mechanism through which they disrupt lipid raft structures differently. In this study, we first established two bilayer membrane models of different composition, the liquid-ordered (Lo) membrane containing cholesterol and sphingomyelin representing a raft domain, and the liquid-disordered (Ld) membrane containing phosphatidylcholine representing a nonraft domain; the surface behavior and consequent interaction of three representative polyphenols (one, a monomeric phenol and the other two, dimeric phenols) with the two bilayer membrane models were then investigated, computationally, through molecular dynamics simulations. The dimeric polyphenols were found to bind to both the Ld and Lo membranes through extensive hydrogen bonding, for the case of the Ld membrane penetrating deeper within the membrane than monophenol, but for the case of the Lo membrane locating predominantly to the lipid headgroups similar to monophenol. Moreover, the dimeric polyphenols exhibited significantly prolonged binding times in both Ld and Lo membranes with a more pronounced effect observed in the Lo membrane. Finally, Langmuir film balance measurements were performed to provide complementary evidence and support the results from the simulations.