The Mechanism of Membrane Fusion and Lipid Flip/Flop Explored with Model Transmembrane Helices

生物过程的多样性，如膜融合和脂质在膜上的翻转/翻转，都是基于蛋白质/脂质相互作用。在以前的工作中，我们已经开发了跨膜螺旋的低复杂性模型- lv肽。这些肽催化膜融合和脂质翻转。这些功能性质取决于螺旋的主链动力学和侧翼残基的电荷状态。在这一建议中，我们提出了关于如何连接功能和结构性质的可测试假设。我们将使用互补的实验方法和模拟来检验这些假设，以阐明膜融合和脂质翻转的机制。特别是，我们将研究一系列lv螺旋与化学上不同的脂质相互作用的能力。首先，这些TMD/脂质相互作用可能导致脂质张开，从而引发膜融合。其次，我们将评估这些相互作用的共价稳定是否促进了脂质翻转，这将支持PC脂质在无序膜域内翻转的观点。第三，我们将测试一个新概念，其中PE脂质的翻转是通过TM螺旋和脂质的耦合膜易位实现的。

A diversity of biological processes, like membrane fusion and lipid flip/flop across membranes, are based on protein/lipid interactions. In previous work, we have developed low-complexity models - the LV-peptides - of transmembrane helices. These peptides catalyze membrane fusion and lipid flip. These functional properties depend on the backbone dynamics of the helices and the charge state of the flanking residues. In this proposal, we present testable hypotheses as to how the functional and the structural properties could be connected. We will examine these hypotheses using complementary experimental approaches and simulations in order to clarify the mechanism of membrane fusion and lipid flip. In particular, we will examine the capacity of a range of LV-helices to interact with chemically distinct lipids. First, these TMD/lipid interaction could cause lipid splay and thereby initiate membrane fusion. Second, we will assess whether the covalent stabilization of these interactions facilitates lipid flip, which would support the idea that PC lipids flip within disordered membrane domains. Third, we will test a new concept where flip of PE lipids is enabled by a coupled membrane translocation of TM helix and lipids.