Lung Surfactant Pathologies: Study of the Formation of Biomolecular Aggregates

肺表面活性物质是一种由脂类/蛋白质混合物组成的表面活性物质，形成层状结构 结构，即肺泡气/水界面处的朗缪尔单层和板层体内的双层。这个 肺表面活性物质的典型成分是50%的二棕榈酰磷脂酰胆碱(DPPC)，25% 不饱和磷脂酰胆碱、12%的带负电荷的磷脂酰甘油(PG)和8%的 表面活性蛋白质。剩下的5%包括其他类型的脂类和胆固醇。各种病理情况 病情与肺表面活性物质的异常组成水平有关。例如, 早产儿或新生儿肺表面活性物质含量不足会导致呼吸道疾病 窘迫综合征，这是新生儿死亡的一个主要原因。大量使用某些表面活性剂 蛋白质与淀粉样纤维的形成有关，导致一种称为肺病的疾病。 肺泡蛋白沉积症(PAP)。此外，肺表面活性物质中脂质的浓度不适当也会导致脂质。 聚集，导致退行性疾病，如急性肺损伤和脂肪沉积症。详细的分子 肺表面活性物质各组分聚集的机制尚不完全清楚。我们 假设表面活性物质蛋白质和/或脂类在特定的脂类层状结构上发生聚集 和热力学状态(组成、温度和表面张力)。我们的主要原因是 假设是，在脂质分层环境中的分子间力可以促进必要的 蛋白质的结构变化，从而形成聚集体。我们还假设将军 可以推导出规则，使我们能够预测肺内聚集体的形成 表面活性剂。为了验证我们的假设，我们建议使用最先进的计算机模拟。 具体地说，将使用和/或开发粗粒度的、联合的和全原子的粒子间势 允许对作用在被调查系统上的力进行准确描述。计算型 蒙特卡洛和分子动力学等技术，加上高效的采样技术，将是 用于测定肺表面活性物质中聚集体形成的性质和条件。 这项研究将有助于阐明肺中脂质/蛋白质聚集体的形成机制。 表面活性剂及其形成与病理的关系。这种关联将有助于该地区的发展 治疗PAP和脂肪沉积的新方法，以及其他与蛋白质聚集相关的方法 疾病。

Pulmonary surfactant is a surface active material composed of a lipids/protein mixture that forms layered structures, i.e. Langmuir monolayer at the alveolar air/water interface and bilayers in lamellar bodies. The typical compositions of pulmonary surfactant are 50% of dipalmitolphosphotidylcholine (DPPC), 25% unsaturated phosphotidylcholine, 12% of the negatively charged phosphatidylglycerol (PG), and 8% of surfactant proteins. The remaining 5% includes other type of lipids and cholesterol. Various pathological conditions 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 respiratory distress syndrome, which is a major cause of neonatal mortality. Large quantities of certain surfactant proteins have been associated to the formation of amyloidal fibrils causing a condition termed pulmonary alveolar proteinosis (PAP). Also, inappropriate concentration of lipids in the lung surfactant can induce lipid aggregation, causing degenerative diseases such as acute lung injury and lipidosis. The detailed molecular mechanism for the aggregation of the various components of lung surfactant is not fully understood. We hypothesize that aggregation of surfactant proteins and/or lipids will occur at certain lipid layered-structure and thermodynamic states (composition, temperature and surface tension). The main reason for our hypothesis is that intermolecular forces in the lipidic-layered environment can promote the necessary structural changes in proteins, and hence the formation of aggregates. We also hypothesize that general rules can be derived allowing us to make predictions regarding the formation of aggregates in lung surfactants. 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 that permit an accurate description of the forces acting on the systems being investigated. Computational techniques such as Monte Carlo and Molecular Dynamics, coupled to efficient sampling techniques, will be used 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 lung surfactants and the correlation of this formation to pathologies. This correlation will help to the development of new approaches for the treatment of PAP and lipidosis, as well as other protein aggregation related diseases.