MOLECULAR MODELING STUDIES OF AMPHIPATHIC MOTIFS

脂蛋白是大的、异质的组装体，并且脂质 成分在生物温度下高度无序。 作为一个 因此，这些复合物无法通过 X 射线研究 晶体学和核磁共振。 在没有直接高 分辨率结构信息，只有计算机模型才会被 能够提供计算两者所需的详细程度 平衡和动态特性。 此类的发展 模型是在上一个资助期间开始的，并且这个 提案描述了该研究的扩展。 在所有的造型中 这里提出，肽将以原子细节表示， 但将使用两种不同的方法来建模 脂质/溶剂环境。 第一种方法使用分子 动力学（MD）模拟，具有明确的全原子模型 脂质和溶剂。 这种方法是最严谨、最准确的 方法对这些系统进行建模，但计算量非常大 要求很高。 第二种方法使用连续统模型 脂质和溶剂，并使用数值方法来求解 泊松-玻尔兹曼方程（适当的方程 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， 促进确定最佳起始几何形状 MD 模拟。 这些方法将应用于研究 两亲性螺旋和β链与平面相互作用 双层以及盘状和球形 HDL 颗粒。 的 目标是开发肽/脂质系统的可靠模型和 对于 HDL 颗粒，协助设计和解释 项目1,3,4的实验，并结合理论 和实验结果，发展综合理论 描述两亲基序与脂质的相互作用。

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.