Computer Simulation of Amphiphilic Aggregates

描述(由申请人提供)：这一竞争性更新要求继续支持克莱恩集团关于膜和膜结合物种的计算机模拟研究，特别强调难以通过标准代码的暴力应用来解决的生物物理问题。具体地说，第一个目标是扩展我们最近开发的膜粗颗粒(CG)模拟模型，以便能够探索由环D，L-α多肽组成的Ghadiri膜活性纳米管的自组装。特别令人感兴趣的是多肽-脂膜相互作用的性质，以及对多肽氨基酸残基和脂类组成的选择的依赖。要探索的一个关键基序是使用环肽封端亚单位来产生具有定制性质的异构体组装。第二个目标将使用CG模型来研究脂类分类和膜介导的蛋白质聚集。目的是阐明蛋白质如何移动脂质，以及脂质如何移动蛋白质来改变局部双层膜的稳定性，从而允许囊泡萌发和膜融合所需的曲率。第三个目标是了解水溶性双嵌段共聚物胶束如何影响合成疏水分子在生物膜上的转移。重点放在聚合物胶束的包封性及其与脂双层的相互作用上。在第四个也是最后一个目标中，将应用新的分子动力学模拟方法来深入了解离子通道中的门控机制。第一个目标将是ClC氯通道，其结构最近由MacKinnon小组在关闭和开放状态下发表。这些结构表明了一种简单的门控机制，涉及单个氨基酸残基(Glu148)的构象变化，如果正确，应该很容易被新的模拟方法获得。如果这种方法对于这个看似简单的例子确实是成功的，那么就建议解决更困难的系统，例如乙酰胆碱受体孔，Unwin最近提出了一种门控机制。

DESCRIPTION (provided by applicant): This competing renewal is requesting continuing support for the Klein group's computer simulation studies on membranes and membrane-bound species, with special emphasis on biophysical problems difficult to tackle with brute force application of standard codes. Specifically, the first aim is to extend our recently developed coarse grain (CG) simulation model for membranes to be able to explore the self-assembly of Ghadiri's membrane-active nanotubes composed of cyclic D, L-alpha-peptides. Of special interest, is the nature of the peptide - lipid membrane interactions, and the dependence on the choice of peptide amino acid residues and lipid composition. A key motif to be explored is the use of cyclic-peptide capping subunits to generate heteromeric assemblies with tailored properties. The second aim will use the CG model to study lipid sorting and membrane-mediated protein aggregation. The goal is to elucidate how proteins move lipids and lipids move proteins to alter the local bilayer membrane stability, thereby allowing for the curvatures required for vesicle budding and membrane fusion. The third aim is directed to understand how water soluble di-block copolymer micelles affect the translocation of synthetic hydrophobic molecules across biomembranes. The focus is on both the encapsulation by the polymer micelles and their interaction with lipid bilayers. In the fourth and final aim, new molecular dynamics simulation methodologies will be applied to gain insights into the mechanism of gating in ion channels. The first target will be the ClC chloride channel, whose structure was recently published by the MacKinnon group in both the closed and open states. These structures suggested a simple gating mechanism involving a conformational change of a single amino acid residue (Glu148) which, if correct, should be readily accessible to the new simulation methods. If the approach is indeed successful for this apparently simple example, it is proposed to tackle more difficult systems such as the acetylcholine receptor pore, for which Unwin has recently proposed a gating mechanism.