The mechanisms of lipid-protein rearrangements during viral infection.

Membrane fusion and fission are important events in living cell functioning. In spite of the great variety of specific cases, all of these phenomena are probably governed by the same physical principles. The first insight into physics of membrane fusion has been achieved through studies on model lipid systems. These results served as a base for subsequent investigations of the mechanisms of biological fusion. The main objective of this brief review is to expose the landmarks on the pathway of these studies and to discuss problems and perspectives. Fusion is a multistage process that includes transitions between several numbers of the intermediates. It is adopted that in the case of fusion of two planar bilayers, the following stages take place: formation of close inter-membrane contact, appearance of local monolayer bridge called a stalk, expansion of stalk leading to formation of hemifusion diaphragm (HD) and, finally, creation of fusion pore. Note that the stalk is nanoscopic and still an invisible object. However, there are no doubts that some kinds of monolayer bridge exist while its shape and structure, energetic and kinetic properties are unknown. The main results on the mechanism of biological fusion were obtained on the cells expressing fusion protein of influenza virus, hemagglutinin (HA). However, this system has no M1 and M2 proteins of influenza, which are responsible for the release of the genetic material of the virus into the target cell. An experimental system developed in our laboratory allows to monitor the fusion of single virions with lipid bilayer and detect RNA release as well as the role of M1 and M2 in this process. Biological fusion is a result of complicated interplay of lipids and special proteins at nanoscopic range. It seems probable that the first function of the proteins is the preparation of a pre-fusion state also known as membrane docking. Redistribution of the energy between proteins and lipids leads to the creation of so-called dimples accumulating bending energy, which facilitates stalk formation. Probably, proteins participate in the subsequent stages of fusion in the course of a set of downhill conformational changes. Unfortunately, the data on the kinetics of these transitions are not available. Therefore, theoretical analysis is limited by a consideration of lipidic subsystem, while proteins participate as boundary conditions or some superimposed constraints. As a result, taking into account lipid tilting and fusion pore compression, low-energy pathway was proposed, leading directly from modified stalk to pore.