SIMULATION OF SPONTANEOUS PEPTIDE INSERTION AND ASSEMBLY IN EPITHELIAL MEMBRANES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 自发性的多肽插入和自组装在膜上形成功能孔或通道，参与了广泛的生物学功能。尽管这些多肽具有重要的基础和生物医学意义，但在分子水平上对它们的确切作用机制仍知之甚少。这一局限性与以下两个方面有关：(1)缺乏合适的分子建模工具来模拟这种复杂的过程；(2)缺乏简单的多肽系统模型来系统地研究受控条件下的各种因素，以揭示潜在的基本原理。这项研究的长期目标是开发一个多尺度的计算框架，同时开发新的模型多肽系统，以获得对膜多肽插入和自组装的物理原理的分子水平的理解。第一个目标是开发一个灵活的粗粒(CG)蛋白质-脂力场，该力场既有效又现实，足以准确地描述螺旋多肽的构象平衡及其对膜结合和多肽结合的依赖。第二个目标是利用直接CG模拟和自由能计算来了解肽序列、溶液条件和脂类性质如何决定肽在生物膜中的自发插入和组装。折叠或组装在插入中的具体作用将使用两个已建立的模型系统进行研究，包括TMX-1/TMX-3和GPA二聚体。主要的焦点是利用来自甘氨酸受体(M2GlyR)第二跨膜螺旋的两亲性多肽作为一个范例来理解螺旋膜多肽的作用是如何将折叠、插入和组装联系在一起的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Spontaneous peptide insertion and self-assembly to form functional pores or channels in membrane are involved in a wide range of biological functions. Despite the great fundamental and biomedical importance, the precise mechanisms of the actions of these peptides remain poorly understood at molecular level. This limitation is related to both (1) a lack of suitable molecular modeling tools for simulating such complex processes and (2) lack of simple model peptide systems to systematically investigate various factors under controlled conditions to uncover the underlying basic principles. The long-term goal of the proposed studies is to develop a multi-scale computational framework and simultaneously exploit novel model peptide systems to obtain a molecular-level understanding of the physical principles of insertion and self-assembly of membrane peptides. The first aim is to develop a flexible coarse-grained (CG) protein-lipid force field that are both efficient and realistic enough to provide an accurate description of conformational equilibria of helical peptides and its dependence on membrane binding and peptide-peptide associations. The second aim is to utilize direct CG simulations and free energy calculations to understand how peptide sequence, solution conditions and lipid properties determine the spontaneous insertion and assembly of peptides in biological membranes. Specific roles of folding or assembly in insertion will be examined using two established model systems including TMX-1/TMX-3 and the GpA dimer. The main focus is to exploit amphipathic peptides derived the second transmembrane helix of the glycine receptor (M2GlyR) as a paradigm for understanding how folding, insertion and assembly are linked altogether for actions of helical membrane peptides.