Simulations of Biased Agonists in the β2 Adrenergic Receptor with Accelerated Molecular Dynamics

The biased agonism of the G protein-coupled receptors (GPCRs), where in addition to a traditional G protein-signalling pathway a GPCR promotes intracellular signals though ß-arrestin, is a novel paradigm in pharmacology. Biochemical and biophysical studies have suggested that a GPCR forms a distinct ensemble of conformations signalling through the G protein and ß-arrestin. Here we report on the dynamics of the ß2 adrenergic receptor bound to the ß-arrestin and G protein biased agonists and the empty receptor to further characterize the receptor conformational changes caused by biased agonists. We use conventional and accelerated molecular dynamics (aMD) simulations to explore the conformational transitions of the GPCR from the active state to the inactive state. We found that aMD simulations enable monitoring the transition within the nanosecond timescale while capturing the known microscopic characteristics of the inactive states, such as the ionic lock, the inward position of F6.44, and water clusters. Distinct conformational states are shown to be stabilized by each biased agonist. In particular, in simulations of the receptor with the ß-arrestin biased agonist, N-cyclopentylbutanepherine we observe a different pattern of motions in helix 7 when compared to simulations with the G protein biased agonist, Salbutamol that involves perturbations of the network of interactions within the NPxxY motif. Understanding the network of interactions induced by biased ligands and the subsequent receptor conformational shifts will lead to development of more efficient drugs. © 2013 American Chemical Society

Generalized Langevin equation: An efficient approach to nonequilibrium molecular dynamics of open systems

The generalized Langevin equation (GLE) has been recently suggested to simulate the time evolution of classical solid and molecular systems when considering general nonequilibrium processes. In this approach, a part of the whole system (an open system), which interacts and exchanges energy with its dissipative environment, is studied. Because the GLE is derived by projecting out exactly the harmonic environment, the coupling to it is realistic, while the equations of motion are non-Markovian. Although the GLE formalism has already found promising applications, e. g., in nanotribology and as a powerful thermostat for equilibration in classical molecular dynamics simulations, efficient algorithms to solve the GLE for realistic memory kernels are highly nontrivial, especially if the memory kernels decay nonexponentially. This is due to the fact that one has to generate a colored noise and take account of the memory effects in a consistent manner. In this paper, we present a simple, yet efficient, algorithm for solving the GLE for practical memory kernels and we demonstrate its capability for the exactly solvable case of a harmonic oscillator coupled to a Debye bath.

Robust nonadiabatic molecular dynamics for metals and insulators

We present a new formulation of the correlated electron-ion dynamics (CEID) scheme, which systematically improves Ehrenfest dynamics by including quantum fluctuations around the mean-field atomic trajectories. We show that the method can simulate models of nonadiabatic electronic transitions and test it against exact integration of the time-dependent Schrodinger equation. Unlike previous formulations of CEID, the accuracy of this scheme depends on a single tunable parameter which sets the level of atomic fluctuations included. The convergence to the exact dynamics by increasing the tunable parameter is demonstrated for a model two level system. This algorithm provides a smooth description of the nonadiabatic electronic transitions which satisfies the kinematic constraints (energy and momentum conservation) and preserves quantum coherence. The applicability of this algorithm to more complex atomic systems is discussed.

Protection of DNA against low-energy electrons by amino acids: A first-principles molecular dynamics study

Using first-principles molecular dynamics simulations, we have investigated the notion that amino acids can play a protective role when DNA is exposed to excess electrons produced by ionizing radiation. In this study we focus on the interaction of glycine with the DNA nucleobase thymine. We studied thymine-glycine dimers and a condensed phase model consisting of one thymine molecule solvated in amorphous glycine. Our results show that the amino acid acts as a protective agent for the nucleobase in two ways. If the excess electron is initially captured by the thymine, then a proton is transferred in a barrier-less way from a neighboring hydrogen-bonded glycine. This stabilizes the excess electron by reducing the net partial charge on the thymine. In the second mechanism the excess electron is captured by a glycine, which acts as a electron scavenger that prevents electron localization in DNA. Both these mechanisms introduce obstacles to further reactions of the excess electron within a DNA strand, e.g. by raising the free energy barrier associated with strand breaks.

Interactions between pyrazole derived enantiomers and Chiralcel OJ: Prediction of enantiomer absolute configurations and elution order by molecular dynamics simulations

The separation of enantiomers and confirmation of their absolute configurations is significant in the development of chiral drugs. The interactions between the enantiomers of chiral pyrazole derivative and polysaccharide-based chiral stationary phase cellulose tris(4-methylbenzoate) (Chiralcel OJ) in seven solvents and under different temperature were studied using molecular dynamics simulations. The results show that solvent effect has remarkable influence on the interactions. Structure analysis discloses that the different interactions between two isomers and chiral stationary phase are dependent on the nature of solvents, which may invert the elution order. The computational method in the present study can be used to predict the elution order and the absolute configurations of enantiomers in HPLC separations and therefore would be valuable in development of chiral drugs.

Development of complex classical force fields through force matching to ab initio data: Application to a room-temperature ionic liquid

Recent experimental neutron diffraction data and ab initio molecular dynamics simulation of the ionic liquid dimethylimidazolium chloride ([dmim]Cl) have provided a structural description of the system at the molecular level. However, partial radial distribution functions calculated from the latter, when compared to previous classical simulation results, highlight some limitations in the structural description offered by force fieldbased simulations. With the availability of ab initio data it is possible to improve the classical description of [dmim]Cl by using the force matching approach, and the strategy for fitting complex force fields in their original functional form is discussed. A self-consistent optimization method for the generation of classical potentials of general functional form is presented and applied, and a force field that better reproduces the observed first principles forces is obtained. When used in simulation, it predicts structural data which reproduces more faithfully that observed in the ab initio studies. Some possible refinements to the technique, its application, and the general suitability of common potential energy functions used within many ionic liquid force fields are discussed.

Evidence of Short-Range Screening in Shock-Compressed Aluminum Plasma

We have investigated the angular variation in elastic x-ray scattering from a dense, laser-shock-compressed aluminum foil. A comparison of the experiment with simulations using an embedded atom potential in a molecular dynamics simulation shows a significantly better agreement than simulations based on an unscreened one-component plasma model. These data illustrate, experimentally, the importance of screening for the dense plasma static structure factor.

Phase Behaviour, Interactions, and Structural Studies of (Amines+Ionic Liquids) Binary Mixtures

We present a study on the phase equilibrium behaviour of binary mixtures containing two 1-alkyl-3-methylimidazolium bis{(trifluoromethyl)sulfonyl}imide-based ionic liquids, [Cnmim] [NTf2] (n=2 and 4), mixed with diethylamine or triethylamine as a function of temperature and composition using different experimental techniques. Based on this work, two systems showing an LCST and one system with a possible hourglass shape are measured. Their phase behaviours are then correlated and predicted by using Flory–Huggins equations and the UNIQUAC method implemented in Aspen. The potential of the COSMO-RS methodology to predict the phase equilibria was also tested for the binary systems studied. However, this methodology is unable to predict the trends obtained experimentally, limiting its use for systems involving amines in ionic liquids. The liquid-state structure of the binary mixture ([C2mim] [NTf2]+diethylamine) is also investigated by molecular dynamics simulation and neutron diffraction. Finally, the absorption of gaseous ethane by the ([C2mim][NTf2]+diethylamine) binary mixture is determined and compared with that observed in the pure solvents.

Pinning down the solid-state polymorphism of the ionic liquid [bmim][PF6]

The solid-state polymorphism of the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate, [bmim][PF6], has been investigated via low-temperature and high-pressure crystallisation experiments. The samples have been characterised by single-crystal X-ray diffraction, optical microscopy and Raman spectroscopy. The solid-state phase behaviour of the compound is confirmed and clarified with respect to previous phase diagrams. The structures of the previously reported gamma-form, which essentially exhibits a G'T cation conformation, as well as those of the elusive beta- and alpha-forms, are reported. Crystals of the beta-phase are twinned and the structure is heavily disordered; the cation conformation in this form is predominantly TT, though significant contributions from other less frequently encountered conformers are also observed at low temperature and high pressure. The cation conformation in the alpha-form is GT; the presence of the G'T conformer at 193 K in this phase can be eliminated on cooling to 100 K. Whilst X-ray structural data are overall in good agreement with previous interpretations based on Raman and NMR studies, they also reveal a more subtle interplay of intermolecular interactions, which give rise to a wider range of conformers than previously considered.

Anisotropy of single crystal 3C-SiC during nanometric cutting

3C–SiC (the only polytype of SiC that resides in a diamond cubic lattice structure) is a relatively new material that exhibits most of the desirable engineering properties required for advanced electronic applications. The anisotropy exhibited by 3C–SiC during its nanometric cutting is significant, and the potential for its exploitation has yet to be fully investigated. This paper aims to understand the influence of crystal anisotropy of 3C–SiC on its cutting behaviour. A molecular dynamics simulation model was developed to simulate the nanometric cutting of single-crystal 3C–SiC in nine (9) distinct combinations of crystal orientations and cutting directions, i.e. (1?1?1) <-1?1?0>, (1?1?1) <-2?1?1>, (1?1?0) <-1?1?0>, (1?1?0) <0?0?1>, (1?1?0) <1?1?-2>, (0?0?1) <-1?1?0>, (0?0?1) <1?0?0>, (1?1?-2) <1?-1?0> and (1?-2?0) <2?1?0>.

In order to ensure the reliability of the simulation results, two separate simulation trials were carried out with different machining parameters. In the first trial, a cutting tool rake angle of -25°, d/r (uncut chip thickness/cutting edge radius) ratio of 0.57 and cutting velocity of 10 m s-1 were used whereas a second trial was done using a cutting tool rake angle of -30°, d/r ratio of 1 and cutting velocity of 4 m s-1. Both the trials showed similar anisotropic variation.

The simulated orthogonal components of thrust force in 3C–SiC showed a variation of up to 45%, while the resultant cutting forces showed a variation of 37%. This suggests that 3C–SiC is highly anisotropic in its ease of deformation. These results corroborate with the experimentally observed anisotropic variation of 43.6% in Young's modulus of 3C–SiC. The recently developed dislocation extraction algorithm (DXA) [1, 2] was employed to detect the nucleation of dislocations in the MD simulations of varying cutting orientations and cutting directions. Based on the overall analysis, it was found that 3C–SiC offers ease of deformation on either (1?1?1) <-1?1?0>, (1?1?0) <0?0?1>, or (1?0?0) <1?0?0> setups.

Shear instability of nanocrystalline silicon carbide during nanometric cutting

The shear instability of the nanoscrystalline 3C-SiC during nanometric cutting at a cutting speed of 100?m/s has been investigated using molecular dynamics simulation. The deviatoric stress in the cutting zone was found to cause sp3-sp2 disorder resulting in the local formation of SiC-graphene and Herzfeld-Mott transitions of 3C-SiC at much lower transition pressures than that required under pure compression. Besides explaining the ductility of SiC at 1500?K, this is a promising phenomenon in general nanoscale engineering of SiC. It shows that modifying the tetrahedral bonding of 3C-SiC, which would otherwise require sophisticated pressure cells, can be achieved more easily by introducing non-hydrostatic stress conditions.

Influence of microstructure on the cutting behaviour of silicon

We use molecular dynamics simulation to study the mechanisms of plasticity during cutting of monocrystalline and polycrystalline silicon. Three scenarios are considered: (i) cutting a single crystal silicon workpiece with a single crystal diamond tool, (ii) cutting a polysilicon workpiece with a single crystal diamond tool, and (iii) cutting a single crystal silicon workpiece with a polycrystalline diamond tool. A long-range analytical bond order potential is used in the simulations, providing a more accurate picture of the atomic-scale mechanisms of brittle fracture, ductile plasticity, and structural changes in silicon. The MD simulation results show a unique phenomenon of brittle cracking typically inclined at an angle of 45° to 55° to the cut surface, leading to the formation of periodic arrays of nanogrooves in monocrystalline silicon, which is a new insight into previously published results. Furthermore, during cutting, silicon is found to undergo solid-state directional amorphisation without prior Si-I to Si-II (beta tin) transformation, which is in direct contrast to many previously published MD studies on this topic. Our simulations also predict that the propensity for amorphisation is significantly higher in single crystal silicon than in polysilicon, signifying that grain boundaries eases the material removal process.

Topical Review: The current understanding on the diamond machining of silicon carbide

The Glenn Research Centre of NASA, USA (www.grc.nasa.gov/WWW/SiC/, silicon carbide electronics) is in pursuit of realizing bulk manufacturing of silicon carbide (SiC), specifically by mechanical means. Single point diamond turning (SPDT) technology which employs diamond (the hardest naturally-occurring material realized to date) as a cutting tool to cut a workpiece is a highly productive manufacturing process. However, machining SiC using SPDT is a complex process and, while several experimental and analytical studies presented to date aid in the understanding of several critical processes of machining SiC, the current knowledge on the ductile behaviour of SiC is still sparse. This is due to a number of simultaneously occurring physical phenomena that may take place on multiple length and time scales. For example, nucleation of dislocation can take place at small inclusions that are of a few atoms in size and once nucleated, the interaction of these nucleations can manifest stresses on the micrometre length scales. The understanding of how stresses manifest during fracture in the brittle range, or dislocations/phase transformations in the ductile range, is crucial in understanding the brittle–ductile transition in SiC. Furthermore, there is a need to incorporate an appropriate simulation-based approach in the manufacturing research on SiC, owing primarily to the number of uncertainties in the experimental research that includes wear of the cutting tool, poor controllability of the nano-regime machining scale (effective thickness of cut), and coolant effects (interfacial phenomena between the tool, workpiece/chip and coolant), etc. In this review, these two problems are combined together to posit an improved understanding on the current theoretical knowledge on the SPDT of SiC obtained from molecular dynamics simulation.

Twinning anisotropy of tantalum during nanoindentation

Unlike other BCC metals, the plastic deformation of nanocrystalline Tantalum during compression is regulated by deformation twinning. Whether or not this twinning exhibits anisotropy was investigated through simulation of displacement-controlled nanoindentation test using molecular dynamics simulation. MD data was found to correlate well with the experimental data in terms of surface topography and hardness measurements. The mechanism of the transport of material was identified due to the formation and motion of prismatic dislocations loops (edge dislocations) belonging to the 1/2<111> type and <100> type Burgers vector family. Further analysis of crystal defects using a fully automated dislocation extraction algorithm (DXA) illuminated formation and migration of twin boundaries on the (110) and (111) orientation but not on the (010) orientation and most importantly after retraction all the dislocations disappeared on the (110) orientation suggesting twinning to dominate dislocation nucleation in driving plasticity in tantalum. A significant finding was that the maximum shear stress (critical Tresca stress) in the deformation zone exceeded the theoretical shear strength of tantalum (Shear modulus/ 2π~10.03 GPa) on the (010) orientation but was lower than it on the (110) and the (111) orientations. In light to this, the conventional lore of assuming the maximum shear stress being 0.465 times the mean contact pressure was found to break down at atomic scale.