Computer Simulation of Amphiphilic Aggregates

描述（由申请人提供）：这一竞争性的更新要求继续支持克莱因集团对膜和膜结合物种的计算机模拟研究，特别强调难以用标准代码的蛮力应用解决的生物物理问题。具体来说，第一个目标是扩展我们最近开发的粗粒（CG）模拟模型的膜，能够探索的自组装Ghadiri的膜活性的环状D，L-α-肽组成的纳米管。特别感兴趣的是肽-脂质膜相互作用的性质，以及对肽氨基酸残基和脂质组成的选择的依赖性。一个关键的主题是探索使用环状肽加帽亚基产生异聚体组装定制的性能。第二个目标将使用CG模型来研究脂质分选和膜介导的蛋白质聚集。我们的目标是阐明蛋白质如何移动脂质和脂质移动蛋白质，以改变局部双层膜的稳定性，从而允许囊泡出芽和膜融合所需的曲率。第三个目的是了解水溶性二嵌段共聚物胶束如何影响合成的疏水分子跨生物膜的易位。重点是由聚合物胶束的封装和它们与脂质双层的相互作用。在第四个也是最后一个目标中，新的分子动力学模拟方法将被应用于深入了解离子通道中的门控机制。第一个目标将是ClC氯离子通道，其结构最近由MacKinnon小组在封闭和开放状态下发表。这些结构提出了一个简单的门控机制，涉及一个单一的氨基酸残基（Glu 148）的构象变化，如果正确的话，应该很容易获得新的模拟方法。如果这种方法在这个看似简单的例子中确实是成功的，那么它将被用于解决更困难的系统，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.