The influence of a single walled carbon nanotube on the structure of a cholesterol cluster (domain) developed over the surface of the endothelial protein 1LQV has been investigated using the classical molecular dynamics (MD) simulation technique. We have observed a substantial impact of carbon nanotube on the arrangement of the cholesterol domain. The carbon nanotube can drag out cholesterol molecules, remarkable reducing the volume of the domain settled down on the protein.
Cholesterol is one of the most important lipid species in human cells, it is well known to modulate the physical properties of biomembranes. Cholesterol also circulates with the blood stream as a component of lipoproteins and can be found in the lymphatic fluid in the human body. There is a large literature on the role of cholesterol in biosystems [1]. Although cholesterol is essential for the functioning of cell membranes, its excess may prove unhealthy.
For example, this starts the development of domains, later foam cells, subsequently leading to formation of plaque deposition in blood vessels [2]. The search for new methods for removing of excess cholesterol molecules, precursors of plaque deposition in an early phase of atherosclerosis disease, is a vital subject of molecular medicine and our simulations are related to this issue. In this context, we have chosen a carbon nanotube since it is known to be hydrophobic. This is an important property when it comes to intervention in the biosystem, where water is the inherent component. The study of the influence of carbon nanotube on cholesterol is in its infancy, limited so far to the very simple nanosystems where only nanotube and cholesterol molecules appear [3,4]. In this work we made a step towards the investigation of the impact of carbon nanotube on a more realistic, albeit more complicated biosystem fragment. Particularly, we made a reconnaissance study, via computer simulation, of the influence of the carbon nanotube on the dynamics of cholesterol molecules forming a domain around a selected extracellular protein in a water environment. Needless to say, taking into account a level of the complexity of the system studied, only the classical MD technique can be effectively applied, ab initio simulations would require an enormous computational resources.
The molecular dynamics (MD) simulations were performed using the NAMD 2.6 program [5] with the all-atom CHARMM force field [6] in NVT (constant number of particles, constant volume and constant temperature) ensemble at the physiological temperature T = 309 K.
The CHARMM force field includes intramolecular harmonic stretching V bond , harmonic bending V angle , torsional V dihedral terms:
The last two terms in equation (1) describing the total potential energy V total of the system coming from nonbonding interactions: van der Waals forces modeled with the standard Lenard-Jones 12-6 potential V vdW and electrostatic interactions V Coulomb (see Table 1 for the explicit forms of total energy components).
To ensure sufficient energy conservation, the integration time step was set to ∆t=0.5 fs for all simulation runs. The standard NAMD integrator (Brünger-Brooks-Karplus algorithm) was used [4]. As an example, extracellural domain protein 1LQV was chosen (see Protein Data Bank [7]). 1LQV protein appears in the thin layer of cells named endothelium, this layer forms an interface between circulating blood and the rest of the vessel wall. That is why we selected the human protein residing in the innermost layer of a blood artery.
Cholesterol molecules were modeled on the full atomistic level. Fig. 1 presents the model of a cholesterol molecule used in simulation. Atomic charges on cholesterol molecule were taken from [8]. We have chosen to place 21 cholesterol molecules near the surface of the 1LQV protein. Next, to make the environment of the described system similar to that appearing in biological samples, water was added (15*10 3 H 2 O molecules, TIP3 model [9]).
The ensemble consisting of protein, cholesterol and water molecules was equilibrated for 310 6 time steps with periodic boundary conditions in a rectangular simulation box (x = 115 Å, y = 58 Å and z = 78 Å, where x, y and z are the edges of simulation box) [10]. Cutoff distance for all non-bonding interactions was set to 13 Å. After equilibration, the system was simulated for 510 6 time steps (2.5 ns). Trajectories and velocities data were collected every 40 time step.
The aim of our computer experiment was to test whether the carbon nanotube could influence the distribution of cholesterol molecules spread over the protein’s surface. First we have done MD simulations for the system composed of 1LQV endothelial protein, cholesterol and water molecules (without nanotube) and the data were collected for reference purpose.
Next, an open-ended (uncapped), armchair (10, 10) single wall carbon nanotube (SWCNT) of length 60 Å (960 atoms) was added to the system. The carbon nanotube was also modeled on the atomistic level with internal degrees of freedom allowing oscillations of SWCNT’s carbon atoms. As a defalut atom type for carbon nanotube, the CA aromatic carbon CHARMM type was chosen [6,11]. Force field parameters for SWCNT atoms are given in Table 1 (taken from [11]).
Initially, SWCNT was placed at a distance of 14 Å from center of the cholesterol domain and the ensemble was equilibrated during 10 6 time steps. The configuration of the syste
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