A key step in the life cycle of an enveloped virus is the fusion between the viral envelope and the target cell membrane, allowing the viral genetic material to enter the cytoplasm of the host cell. Viral fusion is driven by specific viral fusion proteins which undergo major conformational changes after binding to the host membrane. Although fusion proteins from different viruses show little size, shape, or sequence similarity, all enveloped viruses (such as Influenza, HIV, Dengue and Ebola) share several key structural features. All are trimeric post-fusion and the so-called fusion loops, which interact with the host membrane, are all located on extended arms, suggesting a common mode of action. However, despite their importance, few details regarding how viral fusion proteins operate are known. Those mechanisms that have been proposed are largely speculative.
To shed light on the mechanism of viral fusion, atomistic and coarse-grained molecular dynamics simulations have been used to examine the behaviour of the fusogenic domain of a single Ebola virus fusion protein in the presence of a model eukaryotic membrane. It was found that rather than just the fusion loops, the protein arms containing the loops interacted with the host membrane. Together they formed a flat surface parallel to the membrane. Furthermore, by forcing the structural transition from a pre-fusion to a post-fusion conformation we found that a single fusion protein could drive the formation of a hemifused state involving two membranes (a common fusion intermediate). The importance of this result is that it suggests a single fusion protein is sufficient to induce viral fusion. Not only does this work call into question proposed mechanisms involving multiple fusion proteins acting in concert, it also provides a simple explanation of how apparently different proteins might induce fusion via a similar mechanism.