Simulation of membrane fusion

The MD group has an ongoing interest in simulating vesicle fusion and fission processes. Previous simulations performed on small vesicles support the so-called stalk mechanism where in the initial stages of fusion the two vesicles are bridged by a small lipid stalk which expands radially. Drs. Fuhrmans systematically studied the fusion of larger vesicles and discovered a new fusion pathway in which the stalk bends, casting doubt on the universality of the traditional stalk mechanism (see figure 1). In collaboration with Dr. Kasson (Standford Univ.) the simulations are now extended to include a variety of fusion peptides, a common motif found in key proteins driving viral membrane fusion (and possibly all inter or intracellular fusion events).Using CG models, work has started to mimic the experimentally observed fusion of liposomes induced by fragments of the hemagglutininfusion protein. In collaboration with Dr. Zuhorn (UMCG), Drs. Furhmans and Drs. Siwko are furthermore trying to simulate the fusion of lipoplexes (lipid/DNA complexes) with mimetics of the endosomal membrane to understand the molecular details of the process of DNA uptake. Progress has been made to model some of the key players in this process, such as small fragments of DNA and cationic Saint-2 lipids required in the lipoplex formulation. Related work is performed by Drs. Mueller in collaboration with researchers at the University of Queensland.The initial stages of the activation of the E-protein of Dengue virus, a major tropical pathogen, are investigated. The E-protein, which is activated at low pH, is critical to viral entry into cells. Understanding the structural changes that accompany exposure to low pH is critical not only to elucidating the mechanism by which the virus induces fusion between the viral membrane and the membrane of the host cell but is an important first step in the development of potential antiviral strategies.

Figure: two different pathways observed for the fusion between small liposomes. The upper pathway is the direct transition from a stalk to the hemifused state; the lower pathway involves an intermediate state in which a small inverted micelle becomes temporarily trapped. Both pathways are observed for the same system, indicating that the free energy differences are similar.