Grafting Charged Species to Membrane-Embedded Scaffolds Dramatically Increases the Rate of Bilayer Flipping

Abstract

The cell membrane is a barrier to the passive diffusion of charged molecules due to the chemical properties of the lipid bilayer. Surprisingly, recent experiments have identified processes in which synthetic and biological charged species directly transfer across lipid bilayers on biologically relevant time scales. In particular, amphiphilic nanoparticles have been shown to insert into lipid bilayers, requiring the transport of charged species across the bilayer. The molecular factors facilitating this rapid insertion process remain unknown. In this work, we use atomistic molecular dynamics simulations to calculate the free energy barrier associated with “flipping” charged species across a lipid bilayer for species that are grafted to a membrane-embedded scaffold, such as a membrane-embedded nanoparticle. We find that the free energy barrier for flipping a grafted ligand can be over 7 kcal/mol lower than the barrier for translocating an isolated, equivalent ion, yielding a 5 order of magnitude decrease in the corresponding flipping time scale. Similar results are found for flipping charged species grafted to either nanoparticle or protein scaffolds. These results reveal new mechanistic insight into the flipping of charged macromolecular components that might play an important, yet overlooked, role in signaling and charge transport in biological settings. Furthermore, our results suggest guidelines for the design of synthetic materials capable of rapidly flipping charged moieties across the cell membrane.

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

“…Atomistic molecular dynamics simulations are performed to model the interaction of an amphiphilic MUS:OT NP with a dioleoylphosphatidylcholine (DOPC) bilayer. Following previous work [16, 29, 36, 49, 50], the NP gold core is modeled as a rigid, hollow sphere with a diameter of 2 nm. The mass of missing gold atoms is redistributed to the atoms in the shell.…”

“…To complement experimental measurements, computational methods have emerged as a powerful tool to resolve the molecular details of NP-bilayer interactions. For example, molecular simulations have been used to investigate the binding of NPs to single and multicomponent bilayers [17–21], the wrapping of the bilayer around bound NPs [22–26], the insertion of amphiphilic NPs into the bilayer [16, 27–29], the translocation of NPs across the bilayer [30–36], and the disruption of the bilayer induced by NPs [37–39]. These examples represent only a subset of simulation approaches, with more examples detailed in recent review articles covering this field [40–45].…”

“…These examples represent only a subset of simulation approaches, with more examples detailed in recent review articles covering this field [40–45]. In our prior work, molecular dynamics simulations were used to study the interactions of MUS:OT NPs with single-component lipid bilayers [16, 29, 36]. Unbiased simulations confirmed that a MUS:OT NP spontaneously inserts into the bilayer when placed near the high-curvature edge of a bilayer ribbon, a simulation construct that mimics the edge of a large bilayer defect [16].…”

“…Starting from a configuration in which the NP is inserted in the upper leaflet of the bilayer, we apply biasing forces to flip charged ligands across the bilayer midplane. This procedure allows us to analyze a series of intermediate states in which the distribution of ligands on either side of the membrane varies, representing possible states encountered during bilayer insertion that have not been analyzed in prior studies [16, 28, 29, 36, 48]. We show that sequential ligand flipping relaxes bilayer curvature, decreases the nonpolar solvent-exposed surface area of the NP, and increases favorable interactions between charged ligand end groups and lipid head groups, all driving forces that prefer a fully inserted, membrane-spanning configuration.…”

Synthesis and Properties of New Multilayer Chitosan@layered Double Hydroxide/Drug Loaded Phospholipid Bilayer Nanocomposite Bio-Hybrids

“…It is well known that at room temperature the flip-flop of lipids is too slow to account for the relatively fast process observed here for the liposome intercalation. However, recent modeling results point to the possibility of a large acceleration of the flip-flop of charged molecules (up to 10 4 ) in a bilayer in special conditions [57]. More realistic is a mechanism in which one of the bilayers slides over the second one in a tank-tread-like motion, thanks to the presence of a thin-lubricating water film as observed by Rädler et al [58].…”