Cholesterol is a major component of mammalian cell membranes, and is also found in extracellular lymphatic fluid. While cholesterol is essential to maintain the structure and function of a cell membrane, excess levels can be detrimental. Cholesterol molecules can lodge in the inner lining of blood vessels resulting in the plaque deposition associated with atherosclerosis.
The research team, headed up by Zygmunt Gburski, has performed a range of molecular dynamics (MD) simulations to investigate the influence of CNTs and graphene sheets on cholesterol molecules, both within a cell membrane and lodged around extracellular proteins. The collected results of these studies were recently published in the open-access online bookCarbon Nanotubes – Growth and Applications (see also: Solid State Commun. 150 415).
"Computer modelling and simulations can be used for preliminary studies of biosystems, allowing one to directly observe the dynamics of molecules of interest," explained Gburski. "MD simulations allow you to change the components of the system, simplifying or complicating it, and discover what is really important for the dynamics of the system. In particular, MD simulations are very effective when it comes to the study of nanosystems."
MD simulation over 1.5 ns of a CNT placed near an extracellular protein surrounded by cholesterol molecules. MD simulations
The researchers first examined the influence of CNTs on cholesterol molecules embedded in the phospholipid bilayer that forms the cell membrane. MD simulations were performed at physiological temperature with and without a CNT placed near the membrane.
Examining the mean displacement of the cholesterol molecules revealed that the nanotube's presence increased the motion of the cholesterol molecule from 1.1 to 1.3 Å. But though the cholesterol molecules were slightly attracted by the CNT, they always remained inside the phospholipid bilayer – the nanotube could not remove cholesterol molecules from the cell membrane.
Next, the team studied an extracellular domain protein (1KF9) covered by 40 cholesterol molecules. Preliminary MD simulations showed that the cholesterol molecules clustered together near the protein surface and had little mobility. When the simulation was rerun with a CNT placed near the cholesterol cluster, the molecules' mobility increased – attributed to their attraction to the nanotube overwhelming their tendency to gather on the protein surface.
Cholesterol molecules that were pulled out of the cluster spread in a thin layer over the CNT surface. Removal of the nanotube substantially reduced the number of cholesterol molecules within the cluster. For example, a CNT of 80.5 Å in length pulled out 23 cholesterol molecules, an extraction efficiency of 57%.
In the next step, the researchers studied a more complex (and more realistic) system: cholesterol molecules around an extracellular protein in a water environment. The protein 1LQV was selected as it appears in the endothelium layer that lines the inside of blood arteries.
As seen previously, the motion of the cholesterol molecules was initially restricted by interaction with the protein surface. When the CNT was placed nearby, the molecules could migrate farther, with some moving from the cluster and creating a thin layer around the carbon nanotube. A steered molecular dynamics simulation, in which external forces were applied to pull out the CNT, demonstrated that a 60 Å long CNT pulled out 17 of the 21 cholesterol molecules (80% efficiency).
MD simulation (1 ns) of a CNT being removed from the vicinity of the cholesterol cluster in a water environment (for clarity, the water molecules are not shown).
Finally, the researchers examined the influence of graphene, a one-atom-thick sheet of carbon, on cholesterol molecules spread over the endothelial protein's surface. Placing a graphene sheet (720 carbon atoms) 2.3 nm from the cholesterol-covered 1LQV protein significantly increased the mobility of the cholesterol molecules, reflecting their migration onto the graphene surface. After this migration, a large number of cholesterol molecules were removed from the cluster surrounding the protein.
MD simulation (2.5 ns) of a graphene sheet near to a cholesterol-covered protein.
The researchers concluded that the ability of carbon allotropes to extract cholesterol molecules from the surface of an extracellular protein, while leaving molecules within cell membranes untouched, should be taken into account when searching for future medical devices to treat excess cholesterol.
"Our results could be treated as a kind of virtual nanosurgery in a computer laboratory, using a nanotube or graphene wall as a surgical device, and might trigger some real-life experiments in this field," Gburski told medicalphysicsweb.
"When these succeed, the next step would be clinical investigations. However, we are at the very beginning of this road."