Pulmonary surfactant is a surface active material composed of a lipids/protein mixture that forms layeredstructures, i.e. Langmuir monolayer at the alveolar air/water interface and bilayers in lamellar bodies. Thetypical compositions of pulmonary surfactant are 50% of dipalmitolphosphotidylcholine (DPPC), 25%unsaturated phosphotidylcholine, 12% of the negatively charged phosphatidylglycerol (PG), and 8% ofsurfactant proteins. The remaining 5% includes other type of lipids and cholesterol. Various pathologicalconditions have been associated with abnormal composition levels of pulmonary surfactants. For example,an insufficient amount of pulmonary surfactants in premature or newly born infants causes respiratorydistress syndrome, which is a major cause of neonatal mortality. Large quantities of certain surfactantproteins have been associated to the formation of amyloidal fibrils causing a condition termed pulmonaryalveolar proteinosis (PAP). Also, inappropriate concentration of lipids in the lung surfactant can induce lipidaggregation, causing degenerative diseases such as acute lung injury and lipidosis. The detailed molecularmechanism for the aggregation of the various components of lung surfactant is not fully understood. Wehypothesize that aggregation of surfactant proteins and/or lipids will occur at certain lipid layered-structureand thermodynamic states (composition, temperature and surface tension). The main reason for ourhypothesis is that intermolecular forces in the lipidic-layered environment can promote the necessarystructural changes in proteins, and hence the formation of aggregates. We also hypothesize that generalrules can be derived allowing us to make predictions regarding the formation of aggregates in lungsurfactants. To investigate our hypotheses, we propose to use state-of-the-art computer simulations.Specifically, coarse-grained, united, and all-atom interparticle potentials will be used and/or developed thatpermit an accurate description of the forces acting on the systems being investigated. Computationaltechniques such as Monte Carlo and Molecular Dynamics, coupled to efficient sampling techniques, will beused to determine the properties and conditions for the formation of aggregates in pulmonary surfactants.The research will permit the elucidation of the mechanism of formation of lipid/protein aggregates in lungsurfactants and the correlation of this formation to pathologies. This correlation will help to the developmentof new approaches for the treatment of PAP and lipidosis, as well as other protein aggregation relateddiseases.
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