Membrane Remodeling in Viral Infection and Viral Assembly

在报告这一发现的第一篇论文中，研究了流感病毒破坏靶膜的膜机制，我们确定了FPs是这种破坏的基础：在靶膜中，在没有病毒或甚至其余HA的情况下，加入FP形成可逆孔。在旨在理解FPs作用的化学过程的MD模拟中，出现了第三种玫瑰结：FP通过其侧边链（而不是疏水表面）聚集到FP微域，取代顺式小叶中的脂质。这种聚集结构局部变薄了双分子层，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FPs相互倾斜以进一步稀释剩余的脂质，即使是在FP二聚体下。对于较大的聚集体，这种更水合、更薄的膜结构在一个可以形成脂质孔的小区域内取代脂质双分子层。

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.