Flexible pivoting of the pleckstrin domain domain in dynamin catalyzes fission by affecting membrane properties: Insights into the molecular degrees of freedom

The neuronal dynamin1 functions in the release of synaptic vesicles by orchestrating a process of GTPase-dependent membrane fission. Dynamin1 associates with the plasma membrane-localized phosphatidylinositol-4,5-bisphosphate (PIP2) through the centrally located pleckstrin homology domain (PHD). The PHD is dispensable as fission can be managed even when the PHD-PIP2 interaction is replaced by a generic polyhistidine- or polylysine-lipid interaction. Remarkably however, the absence of the PHD renders a dramatic dampening of the rate of fission. These observations suggest that the PHD-PIP2 interaction could have evolved to expedite fission to fulfill the requirement of rapid kinetics of synaptic vesicle recycling. Here, we use a suite of multiscale modeling approaches that combine atomistic molecular dynamics simulations, mixed-resolution membrane mimetic models, coarse-grained molecular simulations and advanced free-energy sampling (metadynamics) methods to explore PHD-membrane interactions. Our results reveal that; (a) the binding of PHD to PIP2-containing membranes modulates the lipids towards fission-favoring conformations and overall softens the membrane thus rendering it pliable to undergo fission, and (b) that it does so by the association of the PHD in multiple orientations using variable loops as pivots. Together, these insights provide a molecular-level understanding of the catalytic role of the PHD in dynamin-mediated membrane fission.