Understanding the Functional Properties of Lipid Heterogeneity in Pulmonary Surfactant Monolayers at the Atomistic Level

Abstract

Pulmonary surfactant is a complex mixture of lipids and proteins lining the interior of the alveoli, and constitutes the first barrier to both oxygen and pathogens as they progress toward blood circulation. Despite decades of study, the behavior of the pulmonary surfactant at the molecular scale is poorly understood, which hinders the development of effective surfactant replacement therapies, useful in the treatment of several lung-related diseases. In this work, we combined all-atom molecular dynamics simulations, Langmuir trough measurements, and AFM imaging to study synthetic four-component lipid monolayers designed to model protein-free pulmonary surfactant. We characterized the structural and dynamic properties of the monolayers with a special focus on lateral heterogeneity. Remarkably, simulations reproduce almost quantitatively the experimental data on pressure-area isotherms and the presence of lateral heterogeneities highlighted by AFM. Quite surprisingly, the pressure-area isotherms do not show a plateau region, despite the presence of liquid-condensed nanometer-sized domains at surface pressures larger than 20 mN/m. In the simulations, the liquid-condensed domains were small and transient, but they did not coalesce to yield a separate phase. They were only slightly enriched in DPPC and cholesterol, and their chemical composition remained very similar to the overall composition of the monolayer membrane. Instead, they differed from liquid-expanded regions in terms of membrane thickness (in agreement with AFM data), diffusion rates, as well as acyl chain packing and orientation. We hypothesize that such lateral heterogeneities are crucial for lung surfactant function, as they allow both efficient packing, to achieve low surface tension, and sufficient fluidity, critical for rapid adsorption to the air–liquid interface during the breathing cycle.

Structural Effects of Cation Binding to DPPC Monolayers

“…[23][24][25][26] Effectively, the charges of the ions are scaled by a factor of 0.75 and the Lennard-Jones σ parameter is fine-tuned to agree with neutron scattering data. Finally, the OPC water model 18 was recently demonstrated by us to provide good agreement with experimental isotherms of lipid monolayers 19,20 and was hence adapted to this work. Since the ECC ions were parametrized with another water model (SPC/E), we refined their σ parameters so that the first peak in the water-ion radial distribution function agreed with experimental findings (see Table S1 in the SI).…”

“…The ECC lipid model is based on the Lipid14 17 model and correctly describes the adsorption of ECC ions onto the PC head group region. 13 Finally, the OPC water model 18 was recently shown to be able to describe lipid monolayer behavior, 19,20 and thus avoid many of the issues with MD simulations of such systems. 12 With this state-of-the-art set of force fields and in combination with Langmuir trough measurements and vibrational sum frequency generation (VSFG) spectroscopy, we studied the effect of the key cations -Na + and Ca 2+ -on the properties of DPPC monolayers.…”

Simulated Breathing: Application of Molecular Dynamics Simulations to Pulmonary Lung Surfactant

“…This overall compliment of biomolecules gives PS a delicate balance of biophysical properties that allows it to function and play such a vital role in our everyday lives. The most notable properties exhibited are rapid adsorption to the air-liquid interface, efficient compression (during expiration) and expansion (during inhalation) of the film during a breathing cycle, as well as immunological protection [2,10].…”

“…Lipids, containing a polar head and non-polar tails, are amphipathic and thus able to form films in alveoli at the air-liquid interface [10]. Dipalmitoylphosphatidylcholine (DPPC), a saturated lipid component that is the most abundant species in PS, helps the film in reducing surface tension to near-zero values [15].…”

“…However, this saturated component alone would not be able to form a functional PS film. The film requires an unsaturated component, such as 1-palmitoyl-2-oleoyl-snglycero-3-phosphoglycerol (POPG), which lends fluidity to the film [10,18]. A combination of saturated and unsaturated lipids are necessary for a properly functioning PS.…”