SIMULATION OF SPONTANEOUS PEPTIDE INSERTION AND ASSEMBLY IN EPITHELIAL MEMBRANES

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 多肽的自发插入和自组装在细胞膜上形成功能性孔或通道参与了广泛的生物学功能。尽管具有重要的基础和生物医学意义，但这些肽的确切作用机制在分子水平上仍然知之甚少。这种限制与以下两个方面有关：（1）缺乏用于模拟这种复杂过程的合适的分子建模工具，以及（2）缺乏简单的模型肽系统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。提出的研究的长期目标是开发一个多尺度的计算框架，同时利用新的模型肽系统，以获得膜肽的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度（CG）蛋白质-脂质力场，既有效又现实，足以提供一个准确的描述螺旋肽的构象平衡和依赖膜结合和肽-肽协会。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、溶液条件和脂质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，包括TMX-1/TMX-3和GpA二聚体进行检查。主要的焦点是利用两亲性肽衍生的第二跨膜螺旋的甘氨酸受体（M2 GlyR）作为一个范例，了解如何折叠，插入和组装连接在一起的螺旋膜肽的行动。

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.