MOLECULAR MODELING STUDIES OF AMPHIPATHIC MOTIFS

两亲基序的分子建模研究

• 批准号: 6327707
• 负责人: STEPHEN C. HARVEY
• 金额: $ 17.62万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6327707
• 关键词: amphiphilicity; apolipoprotein B; apolipoproteins; chemical models; cholesterol; computer graphics /printing; computer simulation; conformation; intermolecular interaction; ionic bond; molecular dynamics; phospholipids; protein sequence; protein structure; protein structure function; synthetic peptide

Lipoproteins are large, heterogeneous assemblies, and the lipid component is highly disordered at biological temperatures. As a consequence, these complexes are impossible to study by x-ray crystallography and NMR. In the absence of direct high resolution structural information, only computer models will be able to provide the necessary level of detail for calculating both equilibrium and dynamic properties. The development of such models was begun during the previous grant period, and this proposal describes extensions of that research. In all the modeling proposed here, the peptides will be represented in atomic detail, but two different approaches will be used for modeling the lipid/solvent environment. The first approach uses molecular dynamics (MD) simulations, with explicit all-atom models for the lipid and solvent. This approach is the most rigorous and accurate method for modeling these systems, but it is computationally very demanding. The second approach uses continuum models for the lipid and solvent, and numerical methods are used to solve the Poisson-Boltzmann equation (the appropriate equation for describing electrostatic effects), allowing the determination of solvation free energies. This is a rapid, approximate method, facilitating the determination of the best starting geometries for the MD simulations. These methods will brought to bear on the study of amphipathic helices and beta strands interacting with planar bilayers and with discoidal and spherical HDL particles. The goals are to develop reliable models for peptide/lipid systems and for HDL particles, to assist in the design and interpretation of the experiments of projects 1,3, and 4, and, combining the theoretical and experimental results, to develop a comprehensive theory describing the interactions of amphipathic motifs with lipids.

脂蛋白是大的、异质的集合体， 组分在生物温度下高度无序。 作为 因此，这些复合物不可能通过X射线研究 晶体学和NMR。 在没有直接高 分辨率结构信息，只有计算机模型将 能够提供必要的详细程度， 平衡和动态特性。 发展这种 模型是在前一个赠款期间开始的， 建议描述了该研究的扩展。 在所有的模特中 在这里提出，肽将以原子细节表示， 但两种不同的方法将用于建模， 脂质/溶剂环境。 第一种方法使用分子 动力学（MD）模拟，明确的全原子模型， 脂质和溶剂。 这种方法是最严格和准确的 方法来模拟这些系统，但它是计算非常 要求很高。 第二种方法使用连续模型， 脂质和溶剂，并使用数值方法来解决 Poisson-Boltzmann方程（适用于 描述静电效应），允许确定 溶剂化自由能 这是一种快速、近似的方法， 便于确定用于所述装置的最佳起始几何形状， MD模拟。 这些方法将用于这项研究 两亲螺旋和β链与平面 双层和具有盘状和球形HDL颗粒。 的 目标是为肽/脂质系统开发可靠的模型， 对于HDL颗粒，以协助设计和解释 实验项目1，3，和4，并结合理论 和实验结果，发展一个全面的理论 描述了两亲基序与脂质的相互作用。