MOLECULAR MODELING STUDIES OF AMPHIPATHIC MOTIFS

脂蛋白是大的、不同种类的集合，而脂类 组分在生物温度下高度无序。作为一名 结果，这些络合物是不可能用x射线研究的。 结晶学和核磁共振。在没有直接高压的情况下 解析结构信息，只有计算机模型才会 能够提供计算两者所需的详细程度 平衡性和动态性。这类产品的发展 Models是在前一次赠款期间开始的，这 提案描述了这项研究的扩展。在所有的造型中 在这里提出的，这些多肽将以原子细节表示， 但将使用两种不同的方法对 脂类/溶剂环境。第一种方法使用分子 动力学(MD)模拟，使用显式全原子模型 脂类和溶剂。这种方法是最严谨和准确的 为这些系统建模的方法，但它在计算上非常 要求很高。第二种方法使用连续介质模型来描述 用脂类和溶剂，并用数值方法求解。 泊松-玻尔兹曼方程(适用于 描述静电效应)，允许确定 溶剂自由能。这是一种快速、近似的方法， 便于确定最佳初始几何形状 MD模拟。这些方法将用于这项研究。 两亲性螺旋和β链与平面相互作用 双层结构，具有盘状和球形的高密度脂蛋白颗粒。这个 目标是开发可靠的肽/脂系统模型和 对于高密度脂蛋白粒子，协助设计和解释 方案1、3、4的实验，并结合理论 和实验结果，来发展一个全面的理论 描述两亲性基序与脂类的相互作用。

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.