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: 7284010
• 负责人: GUSTAVO E LOPEZ-QUINONES
• 金额: $ 17.24万
• 依托单位: UNIVERSITY OF PUERTO RICO MAYAGUEZ
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7284010
• 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; Condition; Coupled; Degenerative Disorder; Development; Disease; Environment; Equilibrium; Infant; Ionic Strengths; Lipids; Lipoidosis; Literature; Mechanics; Methods; Modeling; Modification; Molecular; Monitor; Mutation; Neonatal Mortality; Newborn Respiratory Distress Syndrome; Pathology; Peptide Sequence Determination; Phosphatidyl glycerol; Phosphatidylglycerols; Property; Proteins; Pulmonary Alveolar Proteinosis; Pulmonary Surfactants; Research; Sampling; Solutions; Standards of Weights and Measures; Structure; Surface; Surface Tension; System; Techniques; Temperature; Thermodynamics; Water; alveolar lamellar body; base; molecular dynamics; monolayer; novel strategies; programs; protein aggregate; protein aggregation; research study; 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.

肺表面活性剂是一种由脂质/蛋白质混合物组成的表面活性材料，形成了分层 结构，即牙槽空气/水界面和层状体的双层的Langmuir单层。这 肺表面活性剂的典型组成为二硫莫迪磷脂胆碱（DPPC）的50％，25％ 不饱和磷脂胆碱，收费带负电的磷脂酰甘油（PG）的12％，8％ 表面活性剂蛋白。其余5％包括其他类型的脂质和胆固醇。各种病理 条件与肺表面活性剂的异常组成水平有关。例如， 早产或新生婴儿中的肺表面活性剂不足会引起呼吸系统 遇险综合征，这是新生儿死亡率的主要原因。大量某些表面活性剂 蛋白质与形成淀粉样蛋白原纤维的形成有关，导致称为肺的疾病 牙槽蛋白质病（PAP）。同样，肺表面活性剂中脂质的不当浓度会诱导脂质 聚集，引起退行性疾病，例如急性肺损伤和脂肪病。详细的分子 尚未完全了解肺表面活性剂各种成分的聚集机制。我们 假设表面活性剂蛋白和/或脂质的聚集将在某些脂质分层结构处发生 和热力学状态（组成，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。我们还假设这一一般 可以得出规则，使我们能够对肺中聚集的形成做出预测 表面活性剂。为了调查我们的假设，我们建议使用最新的计算机模拟。 具体而言，将使用和/或开发粗粒，联合和全颗粒室内电势 允许对作用于正在研究的系统的力进行准确描述。计算 蒙特卡洛和分子动力学等技术（​​与有效的采样技术耦合）将是 用于确定肺表面活性剂中骨料形成的特性和条件。 该研究将允许阐明肺中脂质/蛋白质聚集体形成机理 表面活性剂和这种形成与病理的相关性。这种相关将有助于发展 用于治疗PAP和脂质病的新方法，以及其他蛋白质聚集 疾病。