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Sumfrequency generation (SFG) vibrational spectroscopy was appliedto study molecular interactions between amantadine and substrate supportedlipid bilayers serving as model cell membranes. Both isotopicallyasymmetric and symmetric lipid bilayers were used in the research.SFG results elucidated how the water-soluble drug, amantadine, influencedthe packing state of each leaflet of a lipid bilayer and how the drugsaffected the lipid flip-flop process. It is difficult to achieve suchdetailed molecular-level information using other analytical techniques.Especially, from the flip-flop rate change of isotopically asymmetriclipid bilayer induced by amantadine, important information on thedrug–membrane interaction mechanism can be derived. The resultsshow that amantadine can be associated with zwitterionic PC bilayersbut has a negligible influence on the flip-flop behavior of PC moleculesunless at high concentrations. Different effects of amantadine onthe lipid bilayer were observed for the negatively charged DPPG bilayer;low concentration amantadine (e.g., 0.20 mM) in the subphase couldimmediately disturb the outer lipid leaflet and then the lipid associatedamantadine molecules gradually reorganize to cause the outer leafletto return to the original orderly packed state. Higher concentrationamantadine (e.g., 5.0 mM) immediately disordered the packing stateof the outer lipid leaflet. For both the high and low concentrationcases, amantadine molecules only bind to the outer PG leaflet andcannot translocate to the inner layer. The presence of amantadinewithin the negatively charged lipid layers has certain implicationsfor using liposomes as drug delivery carriers for amantadine. Besides,by using PC or PG bilayers with both leaflets deuterated, we wereable to examine how amantadine is distributed and/or oriented withinthe lipid bilayer. The present work demonstrates that SFG resultscan provide an in-depth understanding of the molecular mechanismsof interactions between water-soluble drugs and model cell membranes. [ABSTRACT FROM AUTHOR]