Study of Molecular Mechanism of the Interaction Between MEK1/2 and Trametinib with Docking and Molecular Dynamic Simulation.

Trametinib was endorsed by the FDA in 2013 as a single agent for adult melanoma patients. Trametinib inhibits cell growth and proliferation in multiple tumor xenografts by preventing RAF phosphorylation of MEK and thus restricting accumulation of activated MEK. In this study, the focus of investigation was the mechanism of the interaction between trametinib and MEK1/2 via computational simulation. To specify the best interaction site of inhibitor with MEK1/2 based on the interaction energy ranking, first we performed a docking and then we studied the interactions of the ATP-bound MEK with trametinib, with RAF and the complex of the ATP-bound MEK-trametinib with RAF via molecular dynamic simulations. The results showed that trametinib inactivates the enzyme by bonding to a group of amino acids including Lys97/101, SER218/216, Asp208/212, and Met143/147 in MEK1/2. By bonding to the essential amino acids, trametinib inhibits the activity of the enzyme. All in all, the acquired results can be of great use in designing new inhibitors.

Modelling the influence of thermal effects induced by radio frequency electric field on the dynamics of the ATPase nano-biomolecular motors.

We model the dynamics of the F(0) component of the F(0)F(1)-ATPase mitochondrion-based nano-motor operating in a stochastically-fluctuating medium that represents the intracellular environment. The stochastic dynamics are modeled via Langevin equation of motion wherein fluctuations are treated as white noise. We have investigated the influence of an applied alternating electric field on the rotary motion of the F(0) rotor in such an environment. The exposure to the field induces a temperature rise in the mitochondrion's membrane, within which the F(0) is embedded. The external field also induces an electric potential that promotes a change in the mitochondrion's transmembrane potential (TMP). Both the induced temperature and the change in TMP contribute to a change in the dynamics of the F(0). We have found that for external fields in the radio frequency (RF) range, normally present in the environment and encountered by biological systems, the contribution of the induced thermal effects, relative to that of the induced TMP, to the dynamics of the F(0) is more significant. The changes in the dynamics of the F(0) part affect the frequency of the rotary motion of the F(0)F(1)-ATPase protein motor which, in turn, affects the production rate of the ATP molecules.

Computational modeling of a carbon nanotube-based DNA nanosensor.

During the last decade the design of biosensors, based on quantum transport in one-dimensional nanostructures, has developed as an active area of research. Here we investigate the sensing capabilities of a DNA nanosensor, designed as a semiconductor single walled carbon nanotube (SWCNT) connected to two gold electrodes and functionalized with a DNA strand acting as a bio-receptor probe. In particular, we have considered both covalent and non-covalent bonding between the DNA probe and the SWCNT. The optimized atomic structure of the sensor is computed both before and after the receptor attaches itself to the target, which consists of another DNA strand. The sensor's electrical conductance and transmission coefficients are calculated at the equilibrium geometries via the non-equilibrium Green's function scheme combined with the density functional theory in the linear response limit. We demonstrate a sensing efficiency of 70% for the covalently bonded bio-receptor probe, which drops to about 19% for the non-covalently bonded one. These results suggest that a SWCNT may be a promising candidate for a bio-molecular FET sensor.

Atomistic modelling of crack propagation in a randomly rough nano-scale metallic surface.

Molecular dynamics simulations, based on many-body interatomic potentials, are performed to investigate the propagation of a Mode-I (edge) crack in a roughened two-dimensional (2D) (111) plane of a generic lattice for which we adopt the potential parameters pertinent to the elemental Ag. The randomly rough surface is generated with the help of a fractal-based technique referred to as fractional Brownian motion method. We show that fluctuations in the crack velocity, which lead to the phenomenon of crack branching, are also present for crack propagation in rough surfaces. However, as the roughness increases, this phenomenon becomes less pronounced, and another type of velocity fluctuation associated with the roughness of the surface emerges. Furthermore, it is found that as the roughness of the surface increases, the critical stress for the initiation of crack propagation is increased, and the fluctuations in the crack velocity make their appearance sooner.

Computational modeling of an ion-driven nanomotor.

The dynamics of an ion-driven rotary nanomotor, mimicking the F(0) part of the ATPase biomolecular motor, in the presence, and absence, of an external electric field have been simulated via the application of the stochastic molecular dynamics (MD) method. The rotary motion of the proposed motor arises as a result of an ion gradient established between the outer and inner parts of the environment within which the motor is embedded. We show that the operation of this motor can be controlled by such parameters as the amount of the positive ions placed in the stator part of the motor, the density of the positive ions, and the strength and frequency of the applied electric field.

Computational modelling of a non-viscous fluid flow in a multi-walled carbon nanotube modelled as a Timoshenko beam.

In the design of nanotube-based fluidic devices, a critical issue is the effect of the induced vibrations in the nanotube arising from the fluid flow, since these vibrations can promote structural instabilities, such as buckling transitions. It is known that the induced resonant frequencies depend on the fluid flow velocity in a significant manner. We have studied, for the first time, the flow of a non-viscous fluid in stubby multi-walled carbon nanotubes, using the Timoshenko classical beam theory to model the nanotubes as a continuum structure. We have obtained the variations of the resonant frequencies with the fluid flow velocity under several experimentally interesting boundary conditions and aspect ratios of the nanotube. The main finding from our work is that, compared to an Euler-Bernoulli classical beam model of a nanotube, the Timoshenko beam predicts the loss of stability at lower fluid flow velocities.