A Fundamental Cellular Process Explored Using Multiscale Computer Simulation: Protein Interactions Involved in Clathrin Mediated Endocytosis

Material that cannot pass through the cell membrane can be internalized by enveloping the cargo in a membrane vesicle. One of the key pathways through which this occurs is by the formation of a crystalline clathrin protein coat surrounding the vesicle. This clathrin mediated endocytosis is a key regulatory process in all eukaryotic cells and is the primary method for recycling cellular machinery used during synaptic vesicle transmission. An important step in clathrin mediated endocytosis is the formation of the clathrin crystalline coat around the membrane vesicle, which forms as a result of protein-protein interactions. Understanding these interactions on a molecular level could lead to a deeper insight into the regulatory processes involved in endocytosis. Computer simulations of proteins can provide a molecular level insight into key interactions with significant biological relevance. All-atom simulations, however, are limited to length and time scales that may not be biologically relevant. Because of the limitiations of atomistic simulations, we have developed a coarse-grained model of a single clathrin trimer to understand the key protein-protein interactions involved in clathrin cage formation. This highly reductionist model represents hundreds of residues by each coarse-grained site, but still includes the key interactions involved in the formation of clathrin cages. The coarse-grained simulations have been used to study the energetics of cage formation and guide smaller all-atom simulations to understand the chemical interactions involved in the formation of the protein cage.