Lung Surfactant Pathologies: Study of the Formation of Biomolecular Aggregates

肺表面活性剂病理学：生物分子聚集体形成的研究

• 批准号: 8065497
• 负责人: GUSTAVO E LOPEZ-QUINONES
• 金额: $ 14.57万
• 依托单位: UNIVERSITY OF PUERTO RICO MAYAGUEZ
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8065497
• 关键词: Acute Lung Injury; Affect; Air; Alveolar; Amino Acid Sequence; Amino Acids; Arts; Cereals; Charge; Cholesterol; Code; Communities; Computational Technique; Computer Simulation; Computer software; Coupled; Degenerative Disorder; Development; Disease; Environment; Equilibrium; Infant; Ionic Strengths; Lipids; Lipoidosis; Literature; Mechanics; Methods; Modeling; Modification; Molecular; Monitor; Mutation; Neonatal Mortality; Pathology; Peptide Sequence Determination; Phosphatidyl glycerol; Phosphatidylglycerols; Property; Proteins; Pulmonary Alveolar Proteinosis; Pulmonary Surfactants; Research; Sampling; Solutions; Structure; Surface; Surface Tension; System; Techniques; Temperature; Thermodynamics; Water; alveolar lamellar body; base; molecular dynamics; monolayer; novel strategies; premature; programs; protein aggregate; protein aggregation; research study; respiratory distress syndrome; simulation; surfactant

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.

肺表面活性物质是由脂质/蛋白质混合物组成的层状表面活性物质 结构，即肺泡空气/水界面处的朗缪尔单层和层状体中的双层。这 肺表面活性物质的典型成分是50%二棕榈醇磷脂酰胆碱(DPPC)、25% 不饱和磷脂酰胆碱、12% 带负电的磷脂酰甘油 (PG) 和 8% 表面活性蛋白。剩下的 5% 包括其他类型的脂质和胆固醇。各种病理性 这些病症与肺表面活性物质的异常成分水平有关。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，这是新生儿死亡的主要原因。大量的某些表面活性剂 蛋白质与淀粉样原纤维的形成有关，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浓度不当也会诱发脂质 聚集，引起急性肺损伤和脂质沉积症等退行性疾病。详细分子 肺表面活性物质各种成分聚集的机制尚不完全清楚。我们 假设表面活性剂蛋白和/或脂质在某些脂质层状结构中会发生聚集 和热力学状态（成分、温度和表面张力）。我们的主要原因 假设是脂质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。我们还假设一般 可以推导出规则，使我们能够预测肺部聚集体的形成 表面活性剂。为了研究我们的假设，我们建议使用最先进的计算机模拟。 具体来说，将使用和/或开发粗粒度的、统一的和全原子的粒子间势， 允许准确描述作用在正在研究的系统上的力。计算型 蒙特卡罗和分子动力学等技术与有效的采样技术相结合，将 用于确定肺表面活性剂中聚集体形成的性质和条件。 该研究将有助于阐明肺中脂质/蛋白质聚集体的形成机制 表面活性剂以及这种形成与病理学的相关性。这种相关性将有助于发展 治疗 PAP 和脂质沉积症以及其他与蛋白质聚集相关的新方法 疾病。