Simulation studies of membrane fusion and the role of fusion peptides

PhD ceremony: dhr. M. Fuhrmans, 14.45 uur, Academiegebouw, Broerstraat 5, Groningen

Thesis: Simulation studies of membrane fusion and the role of fusion peptides

Promotor(s): prof. S.J. Marrink

Faculty: Mathematics and Natural Sciences

Mixtures of lipids and water form lyotropic phases in which the polar and apolar moieties are separated by an interface lined with the headgroups of the lipid molecules. These phases are fluid-like in the sense that they are very flexible and that the individual lipids possess a high mobility. At the same time, however, their overall shape is relatively stable. This behavior is the basis of all cellular life and a considerable part of biology revolves around the organization of lipid aggregates into membranes surrounding cells and cellular compartments. A complex machinery of proteins and peptides is involved in controlling the fusion and fission of these membranes as well as the transport through them.

This thesis presents insights obtained from computer simulations, taking a closer look at the intermediate stages of membrane fusion and the role of fusion peptides. In particular, molecular dynamics simulations of vesicle fusion are presented, giving evidence for an alternative fusion pathway. In addition, the effects of the Influenza HA fusion peptide on stalk formation and the phase diagram of representative mixtures of lipids and water are studied placing special emphasis on the curvature of the lipid/water interface. A method to analyze the morphology of molecular aggregates using morphological image analysis is presented as well. Finally, the effects of introducing bundling, i.e. relative restraints on groups of molecules, to the SPC water model has been investigated. Bundling is required for the simultaneous representation of water at the fine- and coarse-grained level in multiscale simulations.