Raft registration across bilayers in a molecularly detailed model

Abstract

Coupling between the inner and outer leaflets of a bilayer plays an important role in biomembrane function, particularly in inducing and registering rafts across leaflets for various cellular signals. However, mechanisms of raft registration remain elusive and several alternatives have been proposed, ranging from electrostatic coupling to chain interdigitation, cholesterol flip-flop and composition-curvature coupling. A general mechanism has been suggested by recent experiments with mixtures of polymer amphiphiles that exhibit domain registration upon ligand-induced segregation. Here, using coarse grained molecular dynamics (CGMD) simulations that are rooted in atomistics, we show that raft registration arises spontaneously in bilayers with a calcium- or ligand-crosslinked ordered phase segregating from a liquid disordered phase. When rafts are not registered, a thickness mismatch between phases induces a “bump” in the apposing liquid phase leaflet, and it appears that the associated localized curvature change guides rafts together and stabilizes the registered state. The absence of explicit charge in the model and the fact that domain size modulates the strength of transmembrane coupling demonstrate that collective interactions are sufficient for raft registration.