Semiempirical Quantum Mechanical Calculations of Dipolar Interaction between Dipyridamole and Dipalmitoyl Phosphatidyl Choline in Langmuir Monolayers K. Thirumoorthy and N. Nandi* Chemistry Department, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India D. Vollhardt* Max Planck Institute of Colloids and Interfaces, D-14424 Potsdam/Golm, Germany O. N. Oliveira, Jr. Instituto de Fisica de Sa ˜ o Carlos, USP, Cx. Postal 780, 13560-970 Sa ˜ o Carlos, SP, Brazil ReceiVed January 25, 2006. In Final Form: March 30, 2006 Recent studies have shown that dipalmitoyl phosphatidyl choline (DPPC) monolayers respond cooperatively to the presence of dipyridamole (DIP) guest molecules even at small concentrations, which is a signature of molecular recognition. Using semiempirical quantum mechanical calculations for the DIP-DPPC system, we show that the incorporation of DIP causes large changes in the vertical dipole moment of the DIP-DPPC system, which can explain why measurable changes in surface potential are observed experimentally even at very low DIP concentrations. The calculations are also consistent with the anomalous concentration dependence of the surface pressure and surface potential isotherms for DIP-DPPC monolayers. Rather than saturation or a continuous increase in the effects caused by the incorporation of increasing amounts of DIP, the experimentally observed inversion in the behavior of the surface potential as the DIP concentration reaches 0.5 mol % would be caused by a change in DIP conformation, from a vertical arrangement for the DIP rings to a horizontal or intermediate arrangement. The strong dipolar interactions indicated in the calculations may also be the origin of the drastic changes in monolayer morphology seen in fluorescence microscopy images, with triskellion-shaped domains being formed for condensed DIP-DPPC monolayers. 1. Introduction Phospholipid Langmuir monolayers have been widely used as biomimetic model systems to investigate molecular-level inter- actions of biologically relevant molecules such as peptides and pharmaceutical drugs with cell membranes. 1 Despite their simplicity compared to the biological systems, Langmuir monolayers may provide important insight into molecular interactions because the distance between molecules can be easily controlled by compression compared to the 3D systems. In recent works, an interesting feature emerged that is associated with the cooperative response of phospholipid monolayers to the presence of guest molecules, where a small concentration of the drug or peptide was already sufficient to cause measurable changes in monolayer properties. 2-4 An example was the interaction of dipyridamole (2,6-bis(diethanolamine)-4,8-dipiperidinopyrimido- [5,4-d] pyrimidine) (DIP), known as a coronary vasodilator, antioxidant, and coactivator of antitumor activity and other drug effects, 1 with L-R-1,2-dipalmitoyl-sn-3-glycero-phosphatidyl choline (DPPC). 2,3 The properties of DPPC monolayers have been well documented in the literature, 5-11 whereas the incor- poration of DIP in DPPC monolayers was investigated using surface pressure-area isotherms, grazing incidence X-ray dif- fraction (GIXD), 2 surface potential measurements, fluorescence microscopy, and Fourier transform infrared reflection absorption spectroscopy (FT-IRRAS). 3 These experimental studies revealed that the presence of DIP markedly changes the properties of a pure DPPC monolayer because of the above-mentioned coopera- tive response. 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