Energy landscape for the insertion of amphiphilic nanoparticles into lipid membranes: A computational study

Abstract

Amphiphilic, monolayer-protected gold nanoparticles (NPs) have been shown to enter cells via a non-endocytic, non-disruptive pathway that could be valuable for biomedical applications. The same NPs were also found to insert into a series of model cell membranes as a precursor to cellular uptake, but the insertion mechanism remains unclear. Previous simulations have demonstrated that an amphiphilic NP can insert into a single leaflet of a planar lipid bilayer, but in this configuration all charged end groups are localized to one side of the bilayer and it is unknown if further insertion is thermodynamically favorable. Here, we use atomistic molecular dynamics simulations to show that an amphiphilic NP can reach the bilayer midplane non-disruptively if charged ligands iteratively “flip” across the bilayer. Ligand flipping is a favorable process that relaxes bilayer curvature, decreases the nonpolar solvent-accessible surface area of the NP monolayer, and increases attractive ligand-lipid electrostatic interactions. Analysis of end group hydration further indicates that iterative ligand flipping can occur on experimentally relevant timescales. Supported by these results, we present a complete energy landscape for the non-disruptive insertion of amphiphilic NPs into lipid bilayers. These findings will help guide the design of NPs to enhance bilayer insertion and non-endocytic cellular uptake, and also provide physical insight into a possible pathway for the translocation of charged biomacromolecules.

The Role of Temperature and Lipid Charge on Intake/Uptake of Cationic Gold Nanoparticles into Lipid Bilayers

“…This configuration is further stabilized by the hydrophobic interaction between the lipid tails and AuNP side chains. Finally, we remark that the limiting step of the AuNP‐membrane interaction, in the transition from the configurations C and D , is the translocation of the charged groups of the AuNP ligands across the bilayer, as shown by Salassi et al However, due to the chosen reaction coordinate which drives the AuNP center‐of‐mass instead of individual side groups, we were not able to observe the iterative “flip” across the bilayer recently predicted by van Lehn and Alexander‐Katz . Due to the complexity of the free energy landscape and the length of the path for describing the AuNP–membrane encapsulation, using the same reaction coordinate for the whole process is a limiting factor.…”

“…Due to the complexity of the free energy landscape and the length of the path for describing the AuNP–membrane encapsulation, using the same reaction coordinate for the whole process is a limiting factor. This specific step of the AuNP internalization process has been investigated with a better tailored reaction coordinate . Their results suggest that several energy barriers between C and B associated with side chain anchoring, which are absent in our PMF, depend on the reaction coordinate chosen due to the time limitations.…”

Anionic nanoparticle-lipid membrane interactions: the protonation of anionic ligands at the membrane surface reduces membrane disruption

“…1) across the membrane. It has been shown that the embedding of the NP into the membrane core happens via a sequence of single-ligand translocation events, all characterized by similar energy barriers 18 . The anchoring barrier of the negatively charged ligand is 76 ± 6 kJ/mol.…”

“…Several computational studies have investigated the molecular mechanisms by which monolayer-protected, anionic Au NPs interact with zwitterionic lipid membranes 14,17,18 . The embedding of the NP into the membrane core is favorable from a thermodynamic point of view, but requires the overcoming of large energy barriers.…”

“…The charged NP ligands need to translocate through the hydrophobic membrane core to anchor the NP to the membrane. The energetic cost of this transition has been estimated similar 17 or lower 18 than the cost of single monovalent ion translocations, depending on the arrangement of the ligands on the NP surface, on the type of lipid and on the force field used to perform the free energy calculation. Both in silico and experimental data support the idea that the presence of defects in lipid packing, such as those found at the edges of bicelles or supported lipid bilayers, may significantly reduce the cost of inserting the NP into the bilayer 19 .…”