Surface Ligand Rigidity Modulates Lipid Raft Affinity of Ultra-small Hydrophobic Nanoparticles: Insights from Molecular Dynamics Simulations
Differential preferences between lipids and proteins drive the formation of dynamical nanoscale membrane domains (lipid rafts), which play key roles in proper functions of the cell. On the other hand, due to the potent physicochemical properties of nanoparticles (NPs), NPs have been widely used in drug delivery, bio-imaging and regulating various essential biological processes of the cell. Hence, in this work, we aim to design ultra-small hydrophobic NPs with tunable raft affinity, which are supposed to partition into the hydrophobic region of lipid membranes and be able to regulate the dynamics of lipid raft domains. A series of µs-scale coarse-grained molecular dynamics simulations and umbrella sampling free energy calculations were performed to investigate the role of ultra-small hydrophobic NPs’ surface ligand rigidity in their raft affinity. Our results indicated that the preferred localizations of NPs can be tuned by adjusting their surface ligand rigidity. Generally, rigid NPs tend to target the raft domain, while soft NPs prefer the interface of raft and non-raft domain. The free energy analysis further indicated that NPs’ surface ligand rigidity can enhance their targeting to lipid raft domains. Besides, we found that these ultra-small NPs had no significant effects on the phase separation of the lipid membrane although they might cause some local interference to surrounding lipids. These results indicate that the targeting to the lipid raft domain can be achieved by NPs’ surface ligand rigidity, which provides helpful insights for further regulations of lipid raft-mediated biological processes.