A DMPA Langmuir Monolayer Study: From Gas to Solid Phase. An Atomistic Description by Molecular Dynamics Simulation J. J. Giner-Casares, † L. Camacho, † M. T. Martı ´n-Romero, † and J. J. Lo ´pez Cascales* ,‡ UniVersidad de Co ´ rdoba, Dpto. Quı ´mica Fı ´sica y Termodina ´ mica Aplicada, Ed. Marie Curie, Campus de Rabanales, 14014 Co ´ rdoba, Spain, and UniVersidad Polite ´ cnica de Cartagena, Centro de Electroquı ´mica y Materiales Inteligentes (CEMI), Aulario II, Campus de Alfonso XIII, 30203 Cartagena, Murcia, Spain ReceiVed October 2, 2007. In Final Form: NoVember 5, 2007 In this work, a DMPA Langmuir monolayer at the air/water interface was studied by molecular dynamics simulations. Thus, an atomistic picture of a Langmuir monolayer was drawn from its expanded gas phase to its final solid condensed one. In this sense, some properties of monolayers that were traditionally poorly or even not reproduced in computer simulations, such as lipid domain formation or pressure-area per lipid isotherm, were properly reproduced in this work. Thus, the physical laws that control the lipid domain formation in the gas phase and the structure of lipid monolayers from the gas to solid condensed phase were studied. Thanks to the atomistic information provided by the molecular dynamics simulations, we were able to add valuable information to the experimental description of these processes and to access experimental data related to the lipid monolayers in their expanded phase, which is difficult or inaccessible to study by experimental techniques. In this sense, properties such as lipids head hydration and lipid structure were studied. 1. Introduction In spite of the pile of publications related to the molecular dynamics simulation of lipid bilayers, 1-5 much less attention has been paid to the study of lipid monolayers at the air/water interface since the pioneering work. 6,7 From our viewpoint, this may be due, in part, to some fundamental barriers, such as inaccuracy in the results when attempts were made to reproduce the π (surface pressure)-lipid area isotherm and the collapse or instability of some models of lipid monolayers that were simulated. In this sense, most of the published papers dealing with Langmuir monolayer simulations either did not calculate the π-area per lipid isotherm 8-10 or overestimated it. 11,12 Also, some of these studies were carried out at unrealistic temperatures compared to experimental conditions. 13 In this context and despite the power and accuracy of some experimental techniques such as X-ray and neutron reflectivity measurements, infrared attenuated total reflectance ATR-IR, and IRRAS studies, 14-18 which provided a detailed description of the Langmuir monolayers in their solid (S) and liquid (LC or LE) states, they were not able to provide an atomistic description of the monolayer. In this regard and because of the limited sensitivity of the above-mentioned experimental techniques, they are not able to provide detailed information about the expanded gas (G) phase. In this work, insight with atomic detail of a Langmuir monolayer formation process is provided. In this sense, amazing agreement between simulation and experimental data is obtained for lipid monolayers in their gas and solid phases. Moreover, a full description of the gas phase is given, which remains unreachable by experimental techniques. In this setting, lipid domain formation was observed during our simulated trajectories, which reproduces this phenomena for lipid monolayers. 19 Thus, we are able to relate the first step in domain formation in the gas phase with experimental data that is not accessible by BAM or fluorescence microscopy. Indeed, as far as we know, this is the first simulation in which such lipid domain formation has been simulated with atomic detail. The Langmuir monolayer was studied using the acid DMPA - (dimyristoylphosphatidic acid) as lipid monolayer formation. This lipid has been widely studied in Langmuir monolayers 20-23 because of, among other factors, its capacity to bear charge, depending on the pH of the solution. Thus, DMPA - was modeled in its monoanionic form by adjusting the solution pH to a value of 7. 21 With the aim of understanding the lipid-lipid and lipid- solvent interactions that control the properties of the lipid monolayers, other relevant properties such as lipid head hydration, * To whom correspondence should be addressed. E-mail: javier.lopez@upct.es. † Universidad de Co ´rdoba. ‡ Universidad Polite ´cnica de Cartagena. (1) van Gunsteren, W. F.; Berendsen, H. J. C. Angew. Chem., Int. Ed. Engl. 1990, 29, 992-1023. (2) Lo ´pez Cascales, J. J.; Garcı ´a de la Torre, J.; Marrink, S.; Berendsen, H. J. Chem. Phys. 1996, 104, 2713-2720. (3) Tieleman, D.; Marrink, S.; Berendsen, H. Biochim. Biophys. Acta 1997, 1331, 235-270. (4) Lo ´pez Cascales, J. J.; Otero, T.; Smith, B.; Gonzalez, C.; Marquez, M. J. Phys. Chem. B 2006, 110, 2358-2363. (5) Pandit, S.; Bostick, D.; Berkowitz, M. Biophys. J. 2003, 84, 3743-3750. (6) Kox, A.; Michels, J.; Wiegel, F. Nature 1980, 287, 317-319. (7) Bo ¨ cker, J.; Schlenkrich, M.; Brickmann, J. J. Phys. Chem. 1992, 96, 9915- 9922. (8) Tarek, M.; Tobias, D.; Klein, M. J. Phys. Chem. 1995, 99, 1393-1402. (9) Dhathathreyan, A.; Collins, S. Langmuir 2002, 18, 928-931. (10) Cuny, V.; Antoni, M.; Arbelot.; Liggieri, L. J. Phys. Chem. B 2004, 108, 13353-13363. (11) Kaznessis, Y.; Kim, S.; R. G. L. Biophys. J. 2002, 82, 1731-1742. (12) Nielsen, S.; Lopez, C.; Moore, P.; Klein, M. J. Phys. Chem. B 2003, 107, 13911-13917. (13) van Buuren, A.; Berendsen, H. Langmuir 1994, 10, 1703-1713. (14) Dutta, P.; Peng, J.; Lin, B.; Prakash, M.; Georgopoulos, P.; Ehrlich, S. Phys. ReV. Lett. 1987, 58, 2228-2231. (15) Mo ¨hwald, H. Phospholipid Monolayers. In Handbook of Biological Physics; Lipowsky, R., Sackmann, E., Eds.; Elsevier Science: Amsterdam, 1995. (16) Dluhy, R. Appl. Spectrosc. ReV. 2000, 35, 315-351. (17) Schalke, M.; Lo ¨sche, M. AdV. Colloid Interface Sci. 2000, 88, 243-274. (18) Dynarowicz-Latka, P. A. D.; Oliveira, O. AdV. 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