Abstract
We studied the interaction of Aspirin (acetylsalicylic acid) with lipid membranes using x-ray diffraction for bilayers containing up to 50 mol% of aspirin. From 2D x-ray intensity maps that cover large areas of reciprocal space we determined the position of the ASA molecules in the phospholipid bilayers and the molecular arrangement of the molecules in the plane of the membranes. We present direct experimental evidence that ASA molecules participate in saturated lipid bilayers of DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine) and preferably reside in the head group region of the membrane. Up to 50 mol% ASA molecules can be dissolved in this type of bilayer before the lateral membrane organization is disturbed and the membranes are found to form an ordered, 2D crystal-like structure. Furthermore, ASA and cholesterol were found to co-exist in saturated lipid bilayers, with the ASA molecules residing in the head group region and the cholesterol molecules participating in the hydrophobic membrane core.
Highlights
The molecular mechanism by which drugs interact with cell membranes has become a central issue in pharmacological science [1]
We used x-ray diffraction to study the interaction between Acetylsalicylic Acid and saturated phospholipid bilayers made of dimyristoylphosphocholine (DMPC)
A 1:1 ratio was found to be the solubility limit of ASA molecules in saturated phospholipid bilayers, with one ASA molecule attached to each lipid head group
Summary
The molecular mechanism by which drugs interact with cell membranes has become a central issue in pharmacological science [1]. From infrared spectroscopy Casal, Martin and Mantsch speculated decades ago that aspirin is located in the lipid head group region of phospholipid bilayers [2]. We used x-ray diffraction to study the interaction between Acetylsalicylic Acid and saturated phospholipid bilayers made of dimyristoylphosphocholine (DMPC). We determine the location of the ASA molecules in the bilayer from electron density profiles perpendicular to the membranes and present the first direct experimental proof that ASA molecules participate in lipid bilayers and are located in the head group region of the bilayers. From wide angle x-ray diffraction experiments the arrangement of lipid and ASA molecules in the plane of the membrane was determined. While in pure DMPC bilayers, lipid head groups and tails show a high degree of positional order, small amounts of ASA lead to a disordered, fluid-like membrane.
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