Membrane Remodeling in Viral Infection and Viral Assembly

在第一篇报告这一发现的论文中，一篇关于流感病毒可以破坏靶膜的膜机制的研究中，我们建立了FP在这种破坏下的基础：在靶膜中，在没有病毒甚至其他HA的情况下，当加入FP时，形成一个可逆孔。在为了解FP的化学作用而精心设计的MD模拟中，出现了第三种花环：FP通过其侧链(而不是其疏水表面)聚集到FP微域中，从而取代顺式小叶中的脂类。这种聚集结构局部地使双层变薄，并显著增加了水进入的可能性。提出了一个新的模型来解释我们的数据，该模型基于FP相互倾斜以进一步稀释即使在FP二聚体下的剩余脂类。对于更大的聚集体，这种更水合的、更薄的膜结构取代了小区域中的脂双层，在那里可以形成脂类孔洞。 第二篇关于流感病毒破坏靶膜的膜机制的论文。融合多肽(FP)结构域是多种包膜病毒中Spike蛋白融合活性所必需的，使病毒能够感染宿主细胞，并且是融合过程中唯一与靶膜脂尾直接相互作用的蛋白质部分。在实验模型膜系统中，有一致的发现这一结构域的孔道，并且，在一定条件下，分离的FFP可以产生孔道。在这里，我们使用分子动力学模拟来研究这些FP诱导的孔是如何在含有不同组成的溶菌脂和POPC的膜中形成的。模拟表明，在高Lysolipid浓度下，毛孔通过混合中间体自发形成，其中FP在顺式小叶中的聚集倾斜，形成横跨小叶的漏斗状结构，并局部减少疏水厚度，必须被水穿过才能形成孔。通过将FP聚集体中的单个FP限制为这种倾斜构象，可以在100 ns的时间尺度上在包括纯POPC在内的较低溶质脂含量的膜中形成孔，比在具有相同组成的双层中的无偏模拟中形成孔要快得多。孔道形成途径类似于高溶脂的自发形成。 浓度。根据膜成分的不同，孔可能是亚稳定的(如POPC中所见)或导致膜破裂。

In the first paper reporting this discovery, a study of the membrane mechanisms by which the influenza virus can disrupt a target membrane, we establish that FPs underly this disruption: in target membranes, a reversible pore forms upon addition of FP in the absence of virus or even the rest of HA. In MD simulations crafted to understand the chemistry by which FPs act, a third kind of rosette emerged: the aggregation of FP via their lateral side chains (not their hydrophobic surfaces) into FP microdomains that displace lipids in the cis leaflet. This aggregated structure locally thinned the bilayer and significantly increased the probability of water entry. A new model is proposed to explain our data based on a tilting of FPs towards each other to further thin the remaining lipids immediately under even an FP dimer. For larger aggregates, this more hydrated, thinner membrane structure replaces the lipid bilayer in a small domain wherein a lipidic pore can form. A second paper on the membrane mechanisms by which the influenza virus can disrupt a target membrane. The fusion peptide (FP) domain is necessary for the fusogenic activity of spike proteins in a variety of enveloped viruses, allowing the virus to infect the host cell, and is the only part of the protein that interacts directly with the target membrane lipid tails during fusion. There are consistent findings of poration by this domain in experimental model membrane systems, and, in certain conditions, the isolated FPs can generate pores. Here, we use molecular dynamics simulations to investigate the specifics of how these FP-induced pores form in membranes with different compositions of lysolipid and POPC. The simulations show that pores form spontaneously at high lysolipid concentrations via hybrid intermediates, where FP aggregates in the cis leaflet tilt to form a funnel-like structure that spans the leaflet and locally reduces the hydrophobic thickness that must be traversed by water to form a pore. By restraining a single FP within an FP aggregate to this tilted conformation, pores can be formed in lower-lysolipid-content membranes, including pure POPC, on the 100-ns timescale, much more rapidly than in unbiased simulations in bilayers with the same composition. The pore formation pathway is similar to the spontaneous formation in high lysolipid concentrations. Depending on the membrane composition, the pores can be metastable (as seen in POPC) or lead to membrane rupture.