Rule-based modelling provides an extendable framework for comparing candidate mechanisms underpinning clathrin polymerisation

Polymerisation of clathrin is a key process that underlies clathrin-mediated endocytosis. Clathrincoated vesicles are responsible for cell internalization of external substances required for normal homeostasis and life-sustaining activity. There are several hypotheses describing formation of closed clathrin structures. According to one of the proposed mechanisms cage formation may start from a flat lattice buildup on the cellular membrane, which is later transformed into a curved structure. Creation of the curved surface requires rearrangement of the lattice, induced by additional molecular mechanisms. Different potential mechanisms require a modeling framework that can be easily modified to compare between them. We created an extendable rule-based model that describes polymerisation of clathrin molecules and various scenarios of cage formation. Using Global Sensitivity Analysis (GSA) we obtained parameter sets describing clathrin pentagon closure and the emergence/production and closure of large-size clathrin cages/vesicles. We were able to demonstrate that the model can reproduce budding of the clathrin cage from an initial flat array.