Structural Dynamics of Amyloid β Peptide Binding to Acetylcholine Receptor and Virtual Screening for Effective Inhibitors

The interaction between Amyloid β (Aβ) peptide and acetylcholine receptor is the key for our understanding of how Aβ fragments block the ion channels within the synapses and thus induce Alzheimer's disease. Here, molecular docking and molecular dynamics (MD) simulations were performed for the structural dynamics of the docking complex consisting of Aβ and α7-nAChR (α7 nicotinic acetylcholine receptor), and the inter-molecular interactions between ligand and receptor were revealed. The results show that A\begin{document}$ \beta_{25-35} $\end{document} is bound to α7-nAChR through hydrogen bonds and complementary shape, and the A\begin{document}$ \beta_{25-35} $\end{document} fragments would easily assemble in the ion channel of \begin{document}$ \alpha $\end{document}7-nAChR, then block the ion transfer process and induce neuronal apoptosis. The simulated amide-I band of A\begin{document}$ \beta_{25-35} $\end{document} in the complex is located at 1650.5 cm\begin{document}$ ^{-1} $\end{document}, indicating the backbone of A\begin{document}$ \beta_{25-35} $\end{document} tends to present random coil conformation, which is consistent with the result obtained from cluster analysis. Currently existing drugs were used as templates for virtual screening, eight new drugs were designed and semi-flexible docking was performed for their performance. The results show that, the interactions between new drugs and \begin{document}$ \alpha $\end{document}7-nAChR are strong enough to inhibit the aggregation of A\begin{document}$ \beta_{25-35} $\end{document} fragments in the ion channel, and also be of great potential in the treatment of Alzheimer's disease.     

用虚量子理论研究重离子束—靶相互作用

本文将虚量了理论用于重离子束与靶相互作用过程中靶原子的Ｋ壳层电子的离子化以及入射重离子的Ｋ壳层电子的激发与离化，这一简单模型所提供的理论结果与实验符合得很好。     

Colour, design and virtual reality at JET

Joint European torus (JET) is the world's largest nuclear fusion research facility investigating the use of nuclear fusion, the process that powers the stars, as a source of clean, limitless electrical energy.The JET machine undergoes an on-going program of upgrades and modifications facilitating a broad scientific program of experimentation. Maintenance of the JET machine is carried out remotely using telemanipulators mounted on a robotic Boom, employing a ‘man in the loop’ approach. The system relies on the use of real time 3D computer graphic models in a ‘virtual reality’ environment for preparation and support of remote-handling operations. Colour is used in this virtual environment to emphasise robots from the vessel environment and to highlight materials, components and systems requiring special care.     

新型虚阴极振荡器的研究

 采用小信号理论，在考虑到透射、反射束电子不同作用下，分析了虚阴极振荡器产生微波的机制，获得了计算微波主频的方法，讨论了增强束波作用效率的方法，并提出一种新型结构的虚阴极振荡器。该振荡器的阳极后放置了一个谐振腔，谐振腔长度很小，虚阴极不能在其中形成，谐振腔受到反射电子束激励并建立强场，场对入射电子进行调制，同时采用同轴结构引出微波。利用2.5D PIC 程序对新型的结构进行了数值模拟，验证了理论分析的正确性。在入射电子束电子能量为520keV和电子束流12.5kA的条件下，获得微波平均功率为1GW，频率为3.66GHz，平均束波转换效率为15.3%。     

Aeroacoustics of musical instruments

Musical sound can be generated from numerical solutions obtained from simple physical models of wind-instruments. We call such synthesizers virtual instruments. Crude caricatures capture the global oscillation behaviour of original instruments, providing the musician with a means of expression comparable to that obtained when playing real instruments. Music is, however, produced by details of the flow which correspond to much smaller temporal and spatial scales than the control of the global oscillation. This suggests that one has to split the physical model into two distinct parts: a simple numerical oscillator followed by a complex sound production module, driven by the output of the first module. We illustrate the background of this idea by a discussion of the clarinet, the human voice, and the trombone.General invited lecture presented by A. Hirschberg at the 12th Italian Congress on Theoretical and Applied Mechanics AIMETA '95, Napoli, 3–6 October 1995.     

Voltammetry as Virtual Potentiometric Sensor in Modelling of a Metal/Ligand System and Refinement of Stability Constants. Part 5

The concept of virtual potential (employed here in modelling operations), a unique experimental setup designed and built in our laboratories, and new regression equations derived for nonlinear fitting of quasi‐reversible direct‐current polarograms were combined with the existing rigorous treatment and refinement of polarographic data to establish reliable metal/ligand models and accurate stability constants for the lead(II)/glycine/OH^? and lead(II)/sarcosine/OH^? systems (sarcosine = N‐methylglycine). In the case of glycine, the complexes [M(HL)], [ML], [ML₂], and [ML₃] were identified, and their stability constants (as log β) were established to be 10.51 ± 0.06, 4.58 ± 0.02, 7.19 ± 0.10, and 9.27 ± 0.02, respectively, the complex [ML₃] being reported here for the first time (Table 2). The system with sarcosine involving [M(HL)], [ML], [ML₂], [ML₃], and [ML₂(OH)₂], with the stability constants (as log β) 11.01 ± 0.04, 4.18 ± 0.03, 7.23 ± 0.03, 9.1 ± 0.3, and 15.97 ± 0.07, respectively, is reported for the first time (Table 3). The log K₁ value for Pb^II with sarcosine is a fraction of a log unit smaller when compared with the Pb^II complex with glycine, in agreement with the literature data for Cu^II, Ni^II, and Zn^II showing the same trend for these two ligands. The proposed nonlinear curve‐fitting operations expand the applicability of polarography to study reliably and conveniently quasi‐reversible, on the polarographic time scale, metal/ligand systems (systems with involved heterogeneous kinetics).     

Focus of high-power microwaves with positive and negative zone plate to increase the receiving power in axial virtual cathode oscillator

We investigated an axial vircator, constructed in a pulsed power generator, called Chundoong, and simulated by a three-dimensional particle-in-cell simulation code, MAGIC. We attempted to increase the receiving power of generated microwaves by directing them at a desired focal point. To do so, a positive and negative zone plates (ZPs) are constructed at main frequency 3.5 GHz, and its focal length is 18.8 cm. The power generated from the virtual cathode is 0.72 GW, from which 24.6 kW is received by receiving antenna without a ZP. The receiving power increased significantly to 45.4 kW (92.6%) and 47.5 kW (84.5%) with positive and negative ZPs, respectively. In addition, both positive and negative ZPs have similar focusing properties for the generated microwaves. The ZP contributes significantly to increasing the receiving power. These findings might be useful for real applications to increase the receiving power at a desired focal point.     

Rational design of inhibitors against LpxA protein of Acinetobacter baumannii using a virtual screening method

BackgroundAcinetobacter baumannii is a highly antimicrobial resistant nosocomial pathogen. Resistance to currently used antibiotics has limited effective drugs against this bacterium. This study aimed to propose a rational inhibitor design against the LpxA protein of A. baumannii using a virtual screening method based on a similar structure of ligands.MethodsIn this study, we targeted LpxA protein, which is involved in the early stage of LPS biosynthesis. In the next step, we used Peptide920 and 1,2- Ethanediol as templates to find similar compounds using Drugbank and Zinc15 webservers, respectively. Subsequently, molecular dynamics (MD) simulations were carried out for LpxA protein and two complexes of ZINC895081 and Macrolactam-1 which represented the highest binding affinity and best conformation. Finally, ADMET properties, water solubility and drug-likeness of the desired compounds were evaluated using SwissADME and DruLiTo softwares.ResultsAccording to considered criteria, Drugbank suggested 5 compunds including Ilomastat, Macrolactam-1, Macrolactam-2, Macimorelin, and Oglufanide. On the other hand, Zinc15 webserver suggested 4 compunds including ZINC895048, ZINC895081, ZINC901061 and ZINC1531008. The result of the HDOCK server and Molegro virtual docker (MVD) showed that Macrolactam-1 and ZINC895081 (Citrate) had the highest docking score. In addition, MD simulations showed that ZINC895081 and Macrolactam-1 ligands have the stable binding to the LpxA protein. According to Lipinski's rule, these two compounds are non-carcinogenic, non-toxic and promising inhibitors against LpxA of A. baumannii.ConclusionIt seems that Macrolactam-1 and ZINC895081 (Citrate) are two valuable promising inhibitors against the LpxA protein of A. baumannii. Further in vitro and in vivo experiments are needed to confirm the capabilities of these proposed compounds against A. baumannii.     

Chromenone-based GSK-3β inhibitors as potential therapeutic targets for cardiovascular diseases: In silico study,molecular dynamics,and ADMET profiles

Glycogen synthase kinase-3 beta (GSK-3β) regulates glycogen metabolism and many different cellulars, including apoptosis, signaling, and neural. It is a crucial therapeutic receptor in heart disease, type 2 diabetes, and Alzheimer's. In this study, using computational methods, flavonoid compounds were investigated for potential inhibitors against GSK-3β. Virtual screening was utilized to investigate flavonoid compounds obtained from the PubChem database. Structure of human heart mitochondria of GSK-3β receptor constructed by homology modeling. Best binding poses were discovered via in silico molecular docking simulation. We surveyed noncovalent interactions among amino acid residues involved in the active site of the modeled Protein and compounds via molecular docking and molecular dynamics (MD).Moreover, ADMET characteristics of best docking conformers have been investigated. The obtained results revealed that compound 1 containing chromenone moiety with binding energy H-bond ?11.4 kcal/mol inhibited effectively binding pocket of the GSK-3β receptor. Moreover, MD simulation analysis (RMSD and radius of gyration indicated complex of the compound and GSK-3β receptor remained stable throughout 100 ns MD simulation, and also analysis of ADMET profiles revealed that selected compounds had good drug-likeness and pharmacokinetic properties. Hence, it was suggested that compounds with chromenone scaffold could potentially inhibit GSK-3β. Structural modification of the chromenone derivatives may result in the discovery of promising candidates for identifying novel drugs as GSK-3β inhibitors.