Effects of Liposome Composition and Size on Protein Corona Formation: Competitive Replacement of Abundant Proteins by High‐Affinity Proteins on the Liposome Surface

Plasma proteins (human serum albumin, immunoglobulin gamma-1, complement C3, and fibrinogen) are simulated with 26 and 36 nm-sized cationic, anionic, and zwitterionic liposomes in water using coarse-grained models. Proteins, initially placed randomly around a liposome, adsorb more significantly onto charged liposomes than onto zwitterionic liposomes through electrostatic interactions with lipid headgroups and hydrophobic interactions with lipid tails, with the greatest adsorption observed on cationic liposomes, in agreement with experimental observations. For zwitterionic liposomes, adsorption is more pronounced on liposomes with smaller headgroups, which also agrees well with experiments. Fewer serum albumin proteins adsorb onto smaller liposomes, consistent with experimental observations, because their relatively weak binding makes them more easily detached at higher bilayer curvature. In simulations of 32 proteins from four different species, although cationic and anionic proteins adsorb onto both cationic and anionic liposomes, they preferentially adsorb to oppositely charged liposomes, indicating the influence of both liposome and protein electrostatics. In particular, diffusivity and binding free-energy calculations show that liposome-protein interactions are energetically stabilized by the replacement of abundant proteins by high-affinity proteins via electrostatic and hydrophobic protein-protein and protein-liposome interactions, to an extent dependent on protein type, supporting the Vroman effect of competitive protein adsorption.