Dependence of fullerene aggregation on lipid saturation due to a balance between entropy and enthalpy

Abstract

It is well-known that fullerenes aggregate inside lipid membranes and that increasing the concentration may lead to (lethal) membrane rupture. It is not known, however, how aggregation and rupture depend on the lipid type, what physical mechanisms control this behavior and what experimental signatures detect such changes in membranes. In this paper, we attempt to answer these questions with molecular simulations, and we show that aggregation and membrane damage depend critically on the degree of saturation of the lipid acyl chains: unsaturated bonds, or “kinks”, impose a subtle but crucial compartmentalization of the bilayer into core and surface regions leading to three distinct fullerene density maxima. In contrast, when the membrane has only fully saturated lipids, fullerenes prefer to be located close to the surface under the head groups until the concentration becomes too large and the fullerenes begin clustering. No clustering is observed in membranes with unsaturated lipids. The presence of “kinks” reverses the free energy balance; although the overall free energy profiles are similar, entropy is the dominant component in unsaturated bilayers whereas enthalpy controls the fully saturated ones. Fully saturated systems show two unique signatures: 1) membrane thickness behaves non-monotonously while the area per lipid increases monotonously. We propose this as a potential reason for the observations of low fullerene concentrations being effective against bacteria. 2) The fullerene-fullerene radial distribution function (RDF) shows splitting of the second peak indicating the emergence short-range order and the importance of the second-nearest neighbor interactions. Similar second peak splitting has been reported in metal glasses.

In silico and in vitro design of cordycepin encapsulation in liposomes for colon cancer treatment

“…The optimized simulation protocols had been intensively tested 73,74 and extensively used. [75][76][77][78] Molecular visualizations were done using the Visual Molecular Dynamics (VMD) soware. 79 Translocation free energy.…”

Formation of aggregates, icosahedral structures and percolation clusters of fullerenes in lipids bilayers: The key role of lipid saturation

“…To the best of our knowledge, most computational studies of fullerenes in lipid membranes deal with single component lipid bilayers. Our previous computational studies [24] show that fullerene aggregation and its physical mechanisms depend on the degree of lipid unsaturation. Open questions include if the position(s) and the number of double bonds are important in fullerene-lipid interactions.…”

“…A number of studies [22,24] show that fullerenes neither aggregate inside lipid bilayers nor cause physical damage. On the other hand, at high concentrations several experimental and computational studies have shown that fullerenes aggregate and may be harmful to biological membranes [24][25][26][27][28][29][30][31]. Even the deceivingly simple question of whether fullerenes aggregate inside membranes remains controversial.…”

Fullerene translocation through peroxidized lipid membranes

“…† The RDFs are found to be in reasonable agreement with previous studies. 39,66 The relative distances of pristine fullerenes have been determined to be similar in all membrane types despite the variations in peak intensities. For example, the peak around 1.05 nm is observed to have higher intensity in peroxidized membranes particularly in DOBU30 and POBU70 than regular DOPC or POPC.…”

“…31,32 Previous computational studies covered the permeation of monomeric fullerene across a lipid bilayer, 33 solvation of fullerene in water, 34 interactions of fullerene dimers inside a bilayer, 35 effects of fullerene on liquid ordering, 36 and fullerene aggregation on lipid membranes. [37][38][39] To our knowledge, however, no study to date has examined the interactions of fullerene molecules with peroxidized lipid membranes, which is a so-called indicator of toxicity. This work provides an insight into the fullerene permeation across lipid membranes depending on the concentration and polarity of fullerene as well as the level of peroxidation of bilayers and suggests that the peroxidation is not likely the cause of membrane integrity disruption in the toxicity mechanism of fullerenes at the concentration levels tested.…”