Abstract
Using coarse-grained membrane simulations we show here that peripheral membrane proteins can form a multitude of higher-order structures due to membrane-mediated interactions. Peripheral membrane proteins characteristically perturb the lipid bilayer in their vicinity which supports the formation of protein assemblies not only within the same but surprisingly also across opposing leaflets of a bilayer. In addition, we also observed the formation of lipid-protein domains on heteregeneous membranes. The clustering ability of proteins, as quantified via the potential of mean force, is enhanced when radius and hydrophobic penetration depth of the proteins increases. Based on our data, we propose that membrane-mediated cluster formation of peripheral proteins supports protein assembly in vivo and hence may play a pivotal role in the formation of templates for signaling cascades and in the emergence of transport intermediates in the secretory pathway.