空间对接机构差动式缓冲系统动力学建模与仿真

对接技术是空间交会对接的关键技术，是建立大型空间站，进行复杂空间作业的前‘提，是我国载人航天工程实施需要迫切解决的问题。对接机构缓冲系统是对接机构的核心部分，决定着对接过程的动力学特性，对实现两航大器安全可靠的对接起着至关重要的作用。对接机构缓冲系统结构和工作原理复杂，是一个多自由度、多变量、高度非线性、多参数祸合的动力学系统，对其进行研究是对接机构研制的核心工作，具有重要的理论和实践意义。本文针对我国载人航天工程正在研制的周边式对接机构差动式缓冲系统进行了以’一厂研究：建立了对接机构缓冲系统的运动学模型，利用Lagrange方程建．立了差动式缓冲系统动力学模型，该模型综合体现了缓冲系统参数对缓冲特性的影响。同时，为缓冲系统实时动力学仿真模型的建立奠定了理论基础。首次建立了对接机构缓冲系统全真可视化实时动力学仿真模型，将约束的真实传动特性反映到仿真模型中，解决了多体动力学建模时山一于对杆自差织，合中两根丝杠佩的适动特性进行近似相等假设所造成的缓冲系统动态特J性失真问题，实现了非线性强棍合系统的实时动态仿真。 利用快速极坐标搜索法，进行了对接环工作空间的确定，基于模态测试方法提出了缓冲系统等效特性的虚拟试验方案，得到了系统的动静态力学性能参数，实现了对对接机构缓冲系统设计的验证。总结出对接机构的最大行程和缓冲阻尼特性的变化规律，建立了机构最大工作行程与机构传动链参数和缓冲元件结构参数的关系模型、系统等效缓冲阻尼特性与缓冲元件性能参数的关系模型，对缓冲系统的深入研究有很大的理论价值，对对接机构缓冲系统的工程设计具有重要的指导意义。建立了缓冲系统的缓冲力与对接环相应姿态的高阶关系模型，有效地提高了对接过程动力学仿真的精度。对接机构缓冲系统的动力学建模与仿真，对空间对接技术的研究，载．人航天一L程的顺利实施具有重要意义。对对接机构的研制具有很人的指导意义，为对接过程动力学研究和对接机构的深入设计奠定了坚实的基础。本文的研究结果，己在上海航天局八0五所对接机构的研制中得到了应用。

AUV水下对接关键技术研究

对国内外主要AUV水下对接系统进行了研究,从对接方式、对接传感器、控制策略、流体干扰和对接失误对策五个方面阐述了AUV水下对接系统的方法、技术现状以及发展趋势.

基于动态混合网格的AUV水下发射与对接数值仿真研究

实现AUV水下发射和对接是解决AUV水下能源补充，水下数据交换和故障检测，实现AUV整个作业过程完全自主的必要前提。而AUV水下发射和对接运动的流场为多个物体运动的流场耦合叠加，对AUV的运动影响不同于无界流场中的单体运动，因此非常有必要研究多体相对运动的绕流场对AUV运动的影响，以实现AUV水下发射和对接的高精度控制，最终实现AUV水下发射和对接工程。 本文为获得AUV水下发射和对接过程数值模拟，针对水下单体、多体的三维大位移运动边界数值仿真问题提出了一种基于动态混合网格数值仿真的方法。主要解决了关键的三个方面问题：1)如何根据流场的特性划分网格拓扑结构，建立适合物体运动的网格；2)如何适应移动边界运动的任意性，建立相应的控制方程，并构建相应的运动区域方法和网格更新方法；3)如何实现移动网格的加速求解并保持计算精度。本文的主要研究内容为： 1) 针对复杂单一域提出一种基于八叉树、Delaunay三角化、层面推进法和前沿推进法的三维混合网格生成方法；对复杂多域提出块混合网格生成方法。数值结果表明，采用本文提出的这两种网格划分方法能适应复杂区域的网格划分，同时能满足流场分布特性，减少网格数量，提高网格划分的质量，提高数值求解精度。 2) 从提高ALE描述的控制方程计算精度方面，提出了三维动态混合网格方 法、改进动态混合网格方法和动态层混合网格方法分别适用于不同运动模式下的网格运动更新。这样不仅能描述任意形式的物体运动，而且能遵守ALE描述控制方程的守恒性，同时提高网格更新的速度，网格更新后的质量和数值求解的精度。 3) 针对多体非定常数值求解耗时，本文提出了动态混合网格并行计算模型，采用基于区域分解的分块耦合并行算法来加速数值求解速度。在不损失计算精度的前提下获得了很高的并行计算加速比。 4) 为了验证移动网格法数值求解的精度，本文首先对单个复杂形状的AUV进行了非定常直航和非定常回转运动的运动边界数值仿真，并用试验和定常求解结果和非定常附加动量源方法验证了移动网格法数值求解的精度。 5) 本文将混合网格方法、移动网格方法和并行计算方法应用到了AUV从发射管发射和对接发射管两个过程的三维大位移运动边界数值仿真中，并用理论值和定常结果验证了数值求解的精度，得到AUV发射过程和对接过程的流场水动力特性，并通过理论和数值试验，提出AUV水下发射和对接方案。

空间对接缓冲试验台助推装置研究

设计了一种用于空间对接缓冲试验台的新型高动态响应助推力模拟装置。介绍了助推装置的机构组成和原理,计算了助推气动系统的响应时间,并分析了助推运动过程。研究表明:该助推装置的响应速度快、精度高,助推力方向实时通过模拟飞行器的质心,满足设计要求。

空间对接缓冲试验台对接环重力平衡技术

在空间对接机构地面缓冲实验平台上,为了模拟空间失重状态,研制了一种高精度、高响应速度的主动对接环重力平衡装置。介绍了对接环重力平衡装置的机构原理。对对接过程随动装置的随动性对系统的干扰进行了详细分析。进行了重力平衡器相关实验,从实验数据和理论分析可以得出:所设计的重力平衡装置完全满足对摩擦阻力和惯性阻力设计指标的要求,重力平衡达到1.1%的精度。

Bioinformatyczna analiza struktury i oddziaływań z substratami metylotransferaz RNA odpowiedzialnych za oporność bakterii na antybiotyki

Wydział Biologii: Instytut Biologii Molekularnej i Biotechnologii

Pesquisa computacional de inibidores de fatores de virulência de bacillus anthracifs

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

A miniaturised arrow ballistic measurement system

A novel miniaturised system for measurement of the in-flight characteristics of an arrow is introduced in this paper. The system allows the user to measure in-flight parameters such as the arrow’s speed, kinetic energy and momentum, arrow drag and vibrations of the arrow shaft. The system consists of electronics, namely a three axis accelerometer, shock switch, microcontroller and EEPROM memory embedded in the arrow tip. The system also includes a docking station for download and processing of in-flight ballistic data from the tip to provide the measured values. With this system, a user can evaluate and optimize their archery equipment setup based on measured ballistic values. Recent test results taken at NIST show the accuracy of the launch velocities to be within +/- 0.59%, when compared with NIST’s most accurate ballistic chronograph.

A kinesin motor in a force-producing conformation.

BACKGROUND: Kinesin motors hydrolyze ATP to produce force and move along microtubules, converting chemical energy into work by a mechanism that is only poorly understood. Key transitions and intermediate states in the process are still structurally uncharacterized, and remain outstanding questions in the field. Perturbing the motor by introducing point mutations could stabilize transitional or unstable states, providing critical information about these rarer states. RESULTS: Here we show that mutation of a single residue in the kinesin-14 Ncd causes the motor to release ADP and hydrolyze ATP faster than wild type, but move more slowly along microtubules in gliding assays, uncoupling nucleotide hydrolysis from force generation. A crystal structure of the motor shows a large rotation of the stalk, a conformation representing a force-producing stroke of Ncd. Three C-terminal residues of Ncd, visible for the first time, interact with the central beta-sheet and dock onto the motor core, forming a structure resembling the kinesin-1 neck linker, which has been proposed to be the primary force-generating mechanical element of kinesin-1. CONCLUSIONS: Force generation by minus-end Ncd involves docking of the C-terminus, which forms a structure resembling the kinesin-1 neck linker. The mechanism by which the plus- and minus-end motors produce force to move to opposite ends of the microtubule appears to involve the same conformational changes, but distinct structural linkers. Unstable ADP binding may destabilize the motor-ADP state, triggering Ncd stalk rotation and C-terminus docking, producing a working stroke of the motor.

A possible model of benzimidazole binding to beta-tubulin disclosed by invoking an inter-domain movement.

Although it is well established that benzimidazole (BZMs) compounds exert their therapeutic effects through binding to helminth beta-tubulin and thus disrupting microtubule-based processes in the parasites, the precise location of the benzimidazole-binding site on the beta-tubulin molecule has yet to be determined. In the present study, we have used previous experimental data as cues to help identify this site. Firstly, benzimidazole resistance has been correlated with a phenylalanine-to-tyrosine substitution at position 200 of Haemonchus contortus beta-tubulin isotype-I. Secondly, site-directed mutagenesis studies, using fungi, have shown that other residues in this region of the protein can influence the interaction of benzimidazoles with beta-tubulin. However, the atomic structure of the alphabeta-tubulin dimer shows that residue 200 and the other implicated residues are buried within the protein. This poses the question: how might benzimidazoles interact with these apparently inaccessible residues? In the present study, we present a mechanism by which those residues generally believed to interact with benzimidazoles may become accessible to the drugs. Furthermore, by docking albendazole-sulphoxide into a modelled H. contortus beta-tubulin molecule we offer a structural explanation for how the mutation conferring benzimidazole resistance in nematodes may act, as well as a possible explanation for the species-specificity of benzimidazole anthelmintics.

Rhodopsin and the Others: A Historical Perspective on Structural Studies of G Protein-Coupled Receptors

The role of rhodopsin as a structural prototype for the study of the whole superfamily of G protein-coupled receptors (GPCRs) is reviewed in an historical perspective. Discovered at the end of the nineteenth century, fully sequenced since the early 1980s, and with direct three-dimensional information available since the 1990s, rhodopsin has served as a platform to gather indirect information on the structure of the other superfamily members. Recent breakthroughs have elicited the solution of the structures of additional receptors, namely the beta 1- and beta 2-adrenergic receptors and the A(2A) adenosine receptor, now providing an opportunity to gauge the accuracy of homology modeling and molecular docking techniques and to perfect the computational protocol. Notably, in coordination with the solution of the structure of the A(2A) adenosine receptor, the first "critical assessment of GPCR structural modeling and docking" has been organized, the results of which highlighted that the construction of accurate models, although challenging, is certainly achievable. The docking of the ligands and the scoring of the poses clearly emerged as the most difficult components. A further goal in the field is certainly to derive the structure of receptors in their signaling state, possibly in complex with agonists. These advances, coupled with the introduction of more sophisticated modeling algorithms and the increase in computer power, raise the expectation for a substantial boost of the robustness and accuracy of computer-aided drug discovery techniques in the coming years.

Discovery of novel Agonists and antagonists of the free fatty acid receptor 1 (FFAR1) using virtual screening

The G-protein-coupled receptor free fatty acid receptor 1 (FFAR1), previously named GPR40, is a possible novel target for the treatment of type 2 diabetes. In an attempt to identify new ligands for this receptor, we performed virtual screening (VS) based on two-dimensional (2D) similarity, three-dimensional (3D) pharmacophore searches, and docking studies by using the structure of known agonists and our model of the ligand binding site, which was validated by mutagenesis. VS of a database of 2.6 million compounds followed by extraction of structural neighbors of functionally confirmed hits resulted in identification of 15 compounds active at FFAR1 either as full agonists, partial agonists, or pure antagonists. Site-directed mutagenesis and docking studies revealed different patterns of ligand-receptor interactions and provided important information on the role of specific amino acids in binding and activation of FFAR1.

Partial agonism, neutral antagonism, and inverse agonism at the human wild-type and constitutively active cholecystokinin-2 receptors

Cholecystokinin receptor-2 (CCK2R) is a G protein receptor that regulates a number of physiological functions. Activation of CCK2R and/or expression of a constitutively active CCK2R variant may contribute to human diseases, including digestive cancers. Search for antagonists of the CCK2R has been an important challenge during the last few years, leading to discovery of a set of chemically distinct compounds. However, several early-discovered antagonists turned out to be partial agonists. In this context, we carried out pharmacological characterization of six CCK2R antagonists using COS-7 cells expressing the human CCK2R or a CCK2R mutant having a robust constitutive activity on inositol phosphates production, and we investigated the molecular mechanisms which, at a CCK2R binding site, account for these features. Results indicated that three compounds, 3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3- yl)-N'-(3-methylphenyl)urea (L365,260), 4-{[2-[[3-(lH-indol-3-yl)-2- methyl-1-oxo-2-[[[1.7.7-trimethyl-bicyclo[2.2.1]hept-2-yl)-oxy]carbonyl]amino] propyl]amino]-1-phenylethyl]amino-4-oxo-[lS-la.2[S*(S*)]4a]} -butanoate N-methyl-D-glucamine (PD135, 158), and (R)-1-naphthalenepropanoic acid, b-[2-[[2-(8-azaspiro-[4.5]dec-8-ylcarbonyl)-4,6-dimethylphenyl]amino]-2- oxoethyl] (CR2945), were partial agonists; one molecule, 1-[(R)-2,3-dihydro-1- (2,3-dihydro-1-(2-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] -3-(3-methylphenyl)urea (YM022), was a neutral antagonist; and two compounds, N-(+)-[1-(adamant-1-ylmethyl)-2,4-dioxo-5-phenyl2,3,4,5-tetrahydro-1H-1, 5-benzodiazepin-3-yl]-N'-phenylurea (GV150,013X) and ([(N-[methoxy-3 phenyl] N-[N-methyl N-phenyl carbamoylmethyl], carbomoylmethyl)-3 ureido]-3-phenyl)2-propionic acid (RPR101,048), were inverse agonists. Furthermore, target- and pharmacophore-based docking of ligands followed by molecular dynamic simulation experiments resulted in consistent motion of aromatic residues belonging to a network presumably important for activation, thus providing the first structural explanations for the different pharmacological profiles of tested compounds. This study confirms that several referenced so-called antagonists are in fact partial agonists, and because of this undesired activity, we suggest that newly generated molecules should be preferred to efficiently block CCK2R-related physiological effects. Furthermore, data on the structural basis for the different pharmacological features of CCK2R ligands will serve to further clarify CCK2R mechanism of activation. Copyright © 2006 The American Society for Pharmacology and Experimental Therapeutics.

Evidence That Interspecies Polymorphism in the Human and Rat Cholecystokinin Receptor-2 Affects Structure of the Binding Site for the Endogenous Agonist Cholecystokinin

The cholecystokinin (CCK) receptor-2 exerts very important central and peripheral functions by binding the neuropeptides cholecystokinin or gastrin. Because this receptor is a potential therapeutic target, great interest has been devoted to the identification of efficient antagonists. However, interspecies genetic polymorphism that does not alter cholecystokinin-induced signaling was shown to markedly affect activity of synthetic ligands. In this context, precise structural study of the agonist binding site on the human cholecystokinin receptor-2 is a prerequisite to elucidating the molecular basis for its activation and to optimizing properties of synthetic ligands. In this study, using site-directed mutagenesis and molecular modeling, we delineated the binding site for CCK on the human cholecystokinin receptor-2 by mutating amino acids corresponding to that of the rat homolog. By doing so, we demonstrated that, although resembling that of rat homolog, the human cholecystokinin receptor-2 binding site also displays important distinct structural features that were demonstrated by susceptibility to several point mutations (F120A, Y189A, H207A). Furthermore, docking of CCK in the human and rat cholecystokinin receptor-2, followed by dynamic simulations, allowed us to propose a plausible structural explanation of the experimentally observed difference between rat and human cholecystokinin-2 receptors.

Probing the mid-gorge of cholinesterases with spacer-modified bivalent quinazolinimines leads to highly potent and selective butyrylcholinesterase inhibitors

The spacer structure of homobivalent quinazolinimes acting as potent acetyl-(AChE)- and butyrylcholinesterase (BChE) inhibitors was chemically modified introducing tertiary amine and acyl-amide moieties, and the activities at both ChEs were evaluated. Molecular docking was applied to explain the data and probe the capacity of the mid-gorge site of both ChEs. The novel spacer structures considerably alter the biological profile of bivalent quinazolinimines with regard to both inhibitory activity and selectivity. Mutual interaction of binding to the various sites of the enzymes was further investigated by applying also different spacer lengths and ring sizes of the alicycle of the tricyclic quinazolinimines. In order to achieve selectivity toward BChE and to improve inhibitory activities, the spacer structure was optimized and identified a highly potent and selective BChE inhibitor. (C) 2010 Elsevier Ltd. All rights reserved.