Differential dynamics of the serotonin(1A) receptor in membrane bilayers of varying cholesterol content revealed by all atom molecular dynamics simulation

The serotonin(1A) receptor belongs to the superfamily of G protein-coupled receptors (GPCRs) and is a potential drug target in neuropsychiatric disorders. The receptor has been shown to require membrane cholesterol for its organization, dynamics and function. Although recent work suggests a close interaction of cholesterol with the receptor, the structural integrity of the serotonin(1A) receptor in the presence of cholesterol has not been explored. In this work, we have carried out all atom molecular dynamics simulations, totaling to 3s, to analyze the effect of cholesterol on the structure and dynamics of the serotonin(1A) receptor. Our results show that the presence of physiologically relevant concentration of membrane cholesterol alters conformational dynamics of the serotonin(1A) receptor and, on an average lowers conformational fluctuations. Our results show that, in general, transmembrane helix VII is most affected by the absence of membrane cholesterol. These results are in overall agreement with experimental data showing enhancement of GPCR stability in the presence of membrane cholesterol. Our results constitute a molecular level understanding of GPCR-cholesterol interaction, and represent an important step in our overall understanding of GPCR function in health and disease.

New insight into the architecture of oxy-anion pocket in unliganded conformation of GAT domains: A MD-simulation study

Human Guanine Monophosphate Synthetase (hGMPS) converts XMP to GMP, and acts as a bifunctional enzyme with N-terminal ``glutaminase'' (GAT) and C-terminal ``synthetase'' domain. The enzyme is identified as a potential target for anticancer and immunosuppressive therapies. GAT domain of enzyme plays central role in metabolism, and contains conserved catalytic residues Cys104, His190, and Glu192. MD simulation studies on GAT domain suggest that position of oxyanion in unliganded conformation is occupied by one conserved water molecule (W1), which also stabilizes that pocket. This position is occupied by a negatively charged atom of the substrate or ligand in ligand bound crystal structures. In fact, MD simulation study of Ser75 to Val indicates that W1 conserved water molecule is stabilized by Ser75, while Thr152, and His190 also act as anchor residues to maintain appropriate architecture of oxyanion pocket through water mediated H-bond interactions. Possibly, four conserved water molecules stabilize oxyanion hole in unliganded state, but they vacate these positions when the enzyme (hGMPS)-substrate complex is formed. Thus this study not only reveals functionally important role of conserved water molecules in GAT domain, but also highlights essential role of other non-catalytic residues such as Ser75 and Thr152 in this enzymatic domain. The results from this computational study could be of interest to experimental community and provide a testable hypothesis for experimental validation. Conserved sites of water molecules near and at oxyanion hole highlight structural importance of water molecules and suggest a rethink of the conventional definition of chemical geometry of inhibitor binding site.

Atomistic Simulation of Stacked Nucleosome Core Particles: Tail Bridging, the H4 Tail, and Effect of Hydrophobic Forces

We report the first atomistic simulation of two stacked nucleosome core particles (NCPs), with an aim to understand, in molecular detail, how they interact, the effect of salt concentration, and how different histone tails contribute to their interaction, with a special emphasis on the H4 tail, known to have the largest stabilizing effect on the NCP-NCP interaction. We do not observe specific K16-mediated interaction between the H4 tail and the H2A-H2B acidic patch, in contrast with the findings from crystallographic studies, but find that the stacking was stable even in the absence of this interaction. We perform simulations with the H4 tail (partially/completely) removed and find that the region between LYS-16 and LYS-20 of the H4 tail holds special importance in mediating the inter-NCP interaction. Performing similar tail-clipped simulations with the H3 tail removed, we compare the roles of the H3 and H4 tails in maintaining the stacking. We discuss the relevance of our simulation results to the bilayer and other liquid-crystalline phases exhibited by NCPs in vitro and, through an analysis of the histone-histone interface, identify the interactions that could possibly stabilize the inter-NCP interaction in these columnar mesophases. Through the mechanical disruption of the stacked nucleosome system using steered molecular dynamics, we quantify the strength of inter-NCP stacking in the presence and absence of salt. We disrupt the stacking at some specific sites of internucleosomal tail-DNA contact and perform a comparative quantification of the binding strengths of various tails in stabilizing the stacking. We also examine how hydrophobic interactions may contribute to the overall stability of the stacking and find a marked difference in the role of hydrophobic forces as compared with electrostatic forces in determining the stability of the stacked nucleosome system.

Efficient simulation and rendering of realistic motion of one-dimensional flexible objects

In gross motion of flexible one-dimensional (1D) objects such as cables, ropes, chains, ribbons and hair, the assumption of constant length is realistic and reasonable. The motion of the object also appears more natural if the motion or disturbance given at one end attenuates along the length of the object. In an earlier work, variational calculus was used to derive natural and length-preserving transformation of planar and spatial curves and implemented for flexible 1D objects discretized with a large number of straight segments. This paper proposes a novel idea to reduce computational effort and enable real-time and realistic simulation of the motion of flexible 1D objects. The key idea is to represent the flexible 1D object as a spline and move the underlying control polygon with much smaller number of segments. To preserve the length of the curve to within a prescribed tolerance as the control polygon is moved, the control polygon is adaptively modified by subdivision and merging. New theoretical results relating the length of the curve and the angle between the adjacent segments of the control polygon are derived for quadratic and cubic splines. Depending on the prescribed tolerance on length error, the theoretical results are used to obtain threshold angles for subdivision and merging. Simulation results for arbitrarily chosen planar and spatial curves whose one end is subjected to generic input motions are provided to illustrate the approach. (C) 2016 Elsevier Ltd. All rights reserved.

Energy conversion in shape memory alloy heat engine - Part II: Simulation

In this paper, a theoretical model proposed in Part I (Zhu et al., 2001a) is used to simulate the behavior of a twin crank NiTi SMA spring based heat engine, which has been experimentally studied by Iwanaga et al. (1988). The simulation results are compared favorably with the measurements. It is found that (1) output torque and heat efficiency decrease as rotation speed increase; (2) both output torque and output power increase with the increase of hot water temperature; (3) at high rotation speed, higher water temperature improves the heat efficiency. On the contrary, at low rotation speed, lower water temperature is more efficient; (4) the effects of initial spring length may not be monotonic as reported. According to the simulation, output torque, output power and heat efficiency increase with the decrease of spring length only in the low rotation speed case. At high rotation speed, the result might be on the contrary.

Molecular dynamics simulation of the role of dislocations in microcrack healing

The molecular dynamics method is used to simulate microcrack healing during heating or/and under compressive stress. A centre microcrack in Cu crystal would be sealed under compressive stress or by heating. The role of compressive stress and heating in crack healing was additive. During microcrack healing, dislocation generation and motion occurred. When there were pre-existing dislocations around the microcrack, the critical temperature or compressive stress necessary for microcrack healing would decrease, and, the higher the number of dislocations, the lower the critical temperature or compressive stress. The critical temperature necessary for microcrack healing depended upon the orientation of the crack plane. For example, the critical temperature for the crack along the (001) plane was the lowest, i.e. 770K.

Direct Numerical Simulation of a Spatially Evolving Supersonic Turbulent Boundary Layer at Ma=6

Direct numerical simulation is carried out for a spatially evolving supersonic turbulent boundary layer at free-stream Mach number 6. To overcome numerical instability, the seventh-order WENO scheme is used for the convection terms of Navier-Stokes equations, and fine mesh is adopted to minimize numerical dissipation. Compressibilty effects on the near-wall turbulent kinetic energy budget are studied. The cross-stream extended self-similarity and scaling exponents including the near-wall region are studied. In high Mach number flows, the coherence vortex structures are arranged to be smoother and streamwised, and the hair-pin vortices are less likely to occur.

Structural Failure Analysis and Numerical Simulation of Micro-Accelerometers under Impulsive Loading

Micromachined accelerometer is a kind of inertial MEMS devices, which usually operate under intensive impact loading. The reliability of micromachined accelerometers is one of the most important performance indices for their design, manufacture and commer

Burst Detection in Turbulent Channel Flows Based on Large Eddy Simulation Databases

Reliable turbulent channel flow databases at several Reynolds numbers have been established by large eddy simulation (LES), with two of them validated by comparing with typical direct numerical simulation (DNS) results. Furthermore, the statistics, such as velocity profile, turbulent intensities and shear stress, were obtained as well as the temporal and spatial structure of turbulent bursts. Based on the LES databases available, the conditional sampling methods are used to detect the structures of burst events. A method to deterimine the grouping parameter from the probability distribution function (pdf) curve of the time separation between ejection events is proposed to avoid the errors in detected results. And thus, the dependence of average burst period on thresholds is considerably weakened. Meanwhile, the average burst-to-bed area ratios are detected. It is found that the Reynolds number exhibits little effect on the burst period and burst-to-bed area ratio.

Monte-Carlo simulation of surface crack growth rate for offshore structural steel E36-Z35

The Monte- Carlo method is used to simulate the surface fatigue crack growth rate for offshore structural steel E36-Z35, and to determine the distributions and relevance of the parameters in the Paris equation. By this method, the time and cost of fatigue crack propagation testing can be reduced. The application of the method is demonstrated by use of four sets of fatigue crack propagation data for offshore structural steel E36-Z35. A comparison of the test data with the theoretical prediction for surface crack growth rate shows the application of the simulation method to the fatigue crack propagation tests is successful.

Two-dimensional simulation of an electron cyclotron resonance plasma source with self-consistent power deposition

Using a refined two-dimensional hybrid-model with self-consistent microwave absorption, we have investigated the change of plasma parameters such as plasma density and ionization rate with the operating conditions. The dependence of the ion current density and ion energy and angle distribution function at the substrate surface vs. the radial position, pressure and microwave power were discussed. Results of our simulation can be compared qualitatively with many experimental measurements.

Intensity Distribution Design for Laser-Induced Thermal Loading Based on Numerical Simulation

To accomplish laser-induced thermal loading simulation tests for pistons,the Gaussian beam was modulated into multi-circular beam with specific intensity distribution.A reverse method was proposed to design the intensity distribution for the laser-induced thermal loading based on finite element(FE) analysis.Firstly,the FE model is improved by alternating parameters of boundary conditions and thermal-physical properties of piston material in a reasonable range,therefore it can simulate the experimental resul...

Molecular Dynamics Simulation of Peeling a DNA Molecule on Substrate

Molecular dynamics (MD) simulations are performed to study adhesion and peeling of a short fragment of single strand DNA (ssDNA) molecule from a graphite surface. The critical peel-off force is found to depend on both the peeling angle and the elasticity of ssDNA. For the short ssDNA strand under investigation, we show that the simulation results can be explained by a continuum model of an adhesive elastic band on substrate. The analysis suggests that it is often the peak value, rather than the mean value, of adhesion energy which determines the peeling of a nanoscale material.