Molecular Dynamics Simulations of Protein Corona Formation on Membrane Surfaces: Effects of Lipid Composition and PEGylation on Selective Plasma Protein Adsorption.

The adsorption of plasma proteins (human serum albumin (SA) and apolipoproteins A-I and E-III) onto various lipid bilayers is simulated. With three different binding orientations for each protein, free energy calculations from umbrella sampling simulations show stronger binding of SA to the bilayer composed of lipids with smaller headgroups and stronger binding of apolipoproteins to the bilayer composed of anionic lipids rather than cationic or zwitterionic lipids, in agreement with experiments. Anionic residues of SA form hydrogen bonds more readily with amine headgroups of lipids than with larger trimethylammonium headgroups, where the cationic nitrogen is sterically hindered. In contrast, cationic residues of apolipoproteins form hydrogen bonds predominantly with anionic phosphate groups of lipids, indicating that protein-bilayer binding is attributed to hydrogen bonds facilitated by electrostatic attraction, depending on the electrostatics and size of lipid headgroups. For lipid bilayers grafted with polyethylene glycol (PEG), the binding strength of SA decreases while that of apolipoproteins increases, consistent with experiments, due to hydrogen bonding and hydrophobic interactions between proteins and PEG. These findings help explain experimental observations regarding the abundance of specific plasma proteins adsorbed onto various liposomes and suggest manipulating lipid composition and PEGylation to attract specific proteins to liposome-based drug carriers.