Membrane remodeling and vesicle formation by biomolecular condensates: A coarse grained simulation study.

Abstract

Intrinsically disordered peptides (IDPs) can undergo liquid-liquid phase separation (LLPS) which is essential for membrane-less organelle formation and intracellular compartmentalization. Several experimental studies observed LLPS at or near the lipid membrane surface, leading to the alteration of the membrane morphology. Processes such as tubulation, endocytosis, exocytosis, and multilamellar membrane formation have also been observed in recent experiments. However, the molecular mechanisms and the governing molecular interactions remain unclear. Here we employ molecular dynamics simulations with different levels of coarse-graining to understand these long timescale processes. We study the coacervation of oppositely charged polypeptide sequences, namely, poly-glutamate (E30) and poly-lysine (K30) mixtures in the presence of lipid bilayers containing different ratios of POPC and POPG, with Martini 3.0 explicit solvent forcefield. We find that at least 20% anionic lipids are required to observe successful events of adsorption, followed by wetting, of the EK-coacervate on the bilayer. Upon wetting, the coacervate produces negative curvature to the bilayer and induces local demixing of lipids. Interestingly, the number of contacts between the polyelectrolytes decreases, unlike previous suggestions that predicted an increased overlap among the polyelectrolytes as the driving force of negative curvature formation. Next, we investigate the sensitivity of membrane deformation to the sequence (or charge patterns) of the IDPs. We observe that the IDPs with segregated charge patterns can remodel the membrane more prominently than IDPs with well-mixed charges. In order to understand the biologically relevant length- and time-scales, we developed a solvent-free coarse grained model for such systems. By tuning the IDP-lipid and IDP-IDP interactions, we observe endocytosis, exocytosis, and multilamellarity induced by the LLPS droplet into the bilayer vesicle.