Modeling of high-affinity binding of the novel atrial anti-arrhythmic agent, vernakalant, to Kv1.5 channels

Vernakalant (RSD1235) is an investigational drug that converts atrial fibrillation rapidly and safely in patients intravenously [Roy et al., J. Am. Coll. Cardiol. 44 (2004) 2355–2361; Roy et al., Circulation 117 (2008) 1518–1525] and maintains sinus rhythm when given orally [Savelieva et al., Europace 10 (2008) 647–665]. Here, modeling using AutoDock4 allowed exploration of potential binding modes of vernakalant to the open-state of the Kv1.5 channel structure. Point mutations were made in the channel model based on earlier patch-clamp studies [Eldstrom et al., Mol. Pharmacol. 72 (2007) 1522–1534] and the docking simulations re-run to evaluate the ability of the docking software to predict changes in drug–channel interactions. Each AutoDock run predicted a binding conformation with an associated value for free energy of binding (FEB) in kcal/mol and an estimated inhibitory concentration (K_i). The most favored conformation had a FEB of −7.12 kcal/mol and a predicted K_i of 6.08 μM (the IC50 for vernakalant is 13.8 μM; [Eldstrom et al., Mol. Pharmacol. 72 (2007) 1522–1534]). This conformation makes contact with all four T480 residues and appears to be clearly positioned to block the channel pore.     

Modeling binding modes of angiotensin II and pseudopeptide analogues to the AT2 receptor

The 3D model of the AT2 receptor has been built employing homology to the transmembrane domain of rhodopsin and a novel build-up procedure for restoring the extracellular loops. By docking a model peptide of angiotensin II in the AT2 receptor model two plausible binding modes were identified. These binding modes were in agreement with most of the suggested ligand-receptor contact points reported in the literature. Eight active and one inactive pseudopeptide angiotensin II analogue were also docked in the receptor and four of the active pseudopeptides were found to mimic the binding mode of angiotensin II. An alternative binding mode for the other four active pseudopeptides was found.     

高速串行总线无源通道建模及校准

高速串行总线无源通道建模的效率及准确性,一直是行业关注的重点。Cadence Sigrity的POWER SI 3D-EM工具,实现了效率与精度的较好结合。本论文先从工具的精度出发,采用精度较高的TRL校准模式来进行仿真测试校准,验证仿真结果的准确性。同时考察工具的分布式并行计算能力,看看在保持足够精度的前提下建模效率的提升。     

Modeling of self-oscillating modes of formation of oil- and gas-fields

This paper presents the results of the computational analysis of complex self-oscillating modes of motion of fluids during the formation of hydrocarbon deposits, held for a number of regions, and determination of their characteristic properties made on this basis.     

Effects of the central potassium ions on the G-quadruplex and stabilizer binding

Human telomeres undertake the structure of intra-molecular parallel G-quadruplex in the presence of K⁺ in eukaryotic cell. Stabilization of the telomere G-quadruplex represents a potential strategy to prevent telomere lengthening by telomerase in cancer therapy. Current work demonstrates that the binding of central K⁺ with the parallel G-quadruplex is a coordinated water directed step-wise process. The K⁺ above the top G-tetrad is prone to leak into environment and the 5′-adenine quickly flips over the top G-tetrad, leading to the bottom gate of G-tetrads as the only viable pathway of K⁺ binding. Present molecular dynamics studies on the two most potent stabilizers RHPS4 and BRACO-19 reveal that the central K⁺ has little influence on the binding conformations of the bound stabilizers. But without the central K⁺, either RHPS4 or BRACO-19 cannot stabilize the structure of G-quadruplex. The binding strength of stabilizers evaluated by the MM-PBSA method follows the order of BRACO-19> RHPS4, which agrees with the experimental results. The difference in binding affinities between RHPS4 and BRACO-19 is probably related to the ability to form intramolecular hydrogen bonds and favorable van del Waals interactions with G-quadruplex. In the models that have one central K⁺ located at the upper/lower binding site, the corresponding top/bottom stacked stabilizers show more favorable binding affinities, indicating the apparent promoting effect of central K⁺ on the stabilizer binding. Our findings provide further insights into the regulatory effect of K⁺ on the G-quadruplex targeted binding, which is meaningful to the development of G-quadruplex stabilizers.     

Modeling of the cage induction motor for symmetrical and asymmetrical modes of operation

This paper presents a numerical model of the three-phase, cage induction motor. This model has been represented as a system of differential equations for flux linkages and angular velocity determination. The differential equations for the flux linkages of the stator windings have been expressed in phase coordinates, while the differential equations for the flux linkages of the rotor circuits have been expressed in orthogonal coordinates, which are fixed in respect with the stator of the motor. The skin effect in the rotor deep bars has been taken in account by representing the rotor as two parallel-connected resistive–inductive circuits. Using the developed model the starting, restarting, running-down modes and three-phase, line-to-line, line-to-ground short-circuits as well as the steady-state conditions can be analyzed. The modes of sudden three-phase short-circuit at the motor terminals, sudden single line-to-ground fault at the high-voltage side of the power supply system and the motor starting process followed by steady-state conditions have been computed.     

基于Simulink的超宽带信道建模

本文构建了IEEE.802.15.3a推荐使用的基于簇方式的模型――修正S-V信道模型。采用MATLAB下的仿真软件包Simulink创建了信道冲激响应模块,并调用了Simulink自带的其他模块构建了完整的信道模型。仿真结果表明信道模型与IEEE.802.15.3a标准信道模型相符合。模块经封装后可以直接作为信道模型供超宽带信道分析和超宽带高速传输研究的计算机前期模拟实验使用。     

空气质量流量传感器的内部流道建模与设计

对于空气质量传感器中的热电阻表面流场分布,需要设计一种合适的内部小流道,能使得热电阻表面的流场分布合理.选择流场湍流模型,仿真分析了直线形壁面和几种圆弧形壁面的内部小流道的流场分布,研究了它们的流场分布特性,确定了热电阻的安装位置.仿真结果表明:与直线形流道相比,圆弧形流道具有较好的同一水平方向的速度一致性和较小的垂直...     

Comparison and analysis of the structures and binding modes of antifungal SE and CYP51 inhibitors

With the abuse of clinical broad-spectrum antimicrobial agents, immunosuppressive agents, chemotherapy drugs, the emergence of pathogenic fungi resistance is more and more frequent. However, there is still no effective treatment for the fungal resistance. Squalenee epoxidase (SE) and 14 α-demethylase (CYP51) are important antifungal drug targets. In order to achieve a deeper insight into the structural characteristics and the action modes of SE and CYP51inhibitors, the homology model of SE (Candida albicans) was constructed using monooxygenase of Pseudomonas aeruginosa as template, and the reliability of model was confirmed by Ramachandran plots and Verify 3D. Subsequently, the molecular superimposition and molecular docking were performed, and the pharmacophore model based on the CYP51 receptor structure was constructed. The results indicate that SE and CYP51 inhibitors have common structural feature with two parts of essential fragments, which are mainly composed of aromatic groups. In addition, the fragment structures of inhibitors are combined in the similar hydrophobic pockets through the hydrophobic forces. The present study provides a deeper perspective to understand the characteristics and docking modes of SE and CYP51 inhibitors. It can be used to guide the optimization and design of SE and CYP51 inhibitors. In addition, it also provides the oretical support for the development of dual target antifungal inhibitors (SE and CYP51), which can help us solve the problem of fungi resistance.     

温度变化对钾离子跨膜通道蛋白传输能力的影响

为了研究温度变化对生物膜跨膜传输能力的影响,本文以钾离子跨膜通道蛋白为研究对象,利用Gromacs分子生物学模拟软件包和Gromos96(53a6)分子力场,通过分子动力模拟技术和伞状采样方法详细研究了300K和275K两个温度条件下钾离子跨膜通道蛋白对单个钾离子的传输机理和Potentials of Means Force自由能在整个传输过程中的变化曲线。分析伞状采样的计算结果表明,温度的下降对钾离子跨膜通道蛋白的传输能力具有较大影响,300K时,钾离子在跨膜通道蛋白中的传输过程是热力学自发过程;然而,当温度下降到275K后,跨膜通道蛋白前沿空腔对钾离子的捕捉能力明显下降,选择性位点的能垒和传输通道的自由能普遍上升,导致跨膜通道蛋白出口的自由能高于其入口的自由能,最终使钾离子跨膜通道蛋白对钾离子传输方向发生逆转。同时该结果还可以对冷害发生的机理和防治给予重要的启示:说明温度下降后,果蔬体内物质传输能力的下降和停滞是造成冷害发生的一个主要原因。     

Theoretical studies on binding modes of copper-based nucleases with DNA

In the present work, molecular simulations were performed for the purpose of predicting the binding modes of four types of copper nucleases (a total 33 compounds) with DNA. Our docking results accurately predicted the groove binding and electrostatic interaction for some copper nucleases with B-DNA. The intercalation modes were also reproduced by “gap DNA”. The obtained results demonstrated that the ligand size, length, functional groups and chelate ring size bound to the copper center could influence the binding affinities of copper nucleases. The binding affinities obtained from the docking calculations herein also replicated results found using MM-PBSA approach. The predicted DNA binding modes of copper nucleases with DNA will ultimately help us to better understand the interaction of copper compounds with DNA.     

钠离子通道开放剂的药效团模型与构效关系研究

采用软件Catalyst的Hip Hop、Hypo Gen方法和Sybyl 6.5的Co MSIA方法,对作用于钠离子通道位点2的一些类似物进行三维药效团模型和三维定量构效关系研究。计算结果表明,构建的药效团模型相关系数为0.946727,Co MSIA模型的交叉验证相关系数(CV_r2)为0.739,方程的相关系数r2为0.981,两者均得到了较佳的预测模型。这些模型可用于对该作用位点的化合物进行作用机理探讨和活性评价,为进一步设计新农药和合成高效低毒的钠离子通道开放剂提供一些理论依据。     

On Numerical Modeling of the Multidimensional Dynamic Systems under Random Perturbations with the 1.5 and 2.0 Orders of Strong Convergence

The paper was devoted to developing numerical methods with the orders 1.5 and 2.0 of strong convergence for the multidimensional dynamic systems under random perturbations obeying stochastic differential Ito equations. Under the assumption of a special mean-square convergence criterion, attention was paid to the methods of numerical modeling of the iterated Ito and Stratonovich stochastic integrals of multiplicities 1 to 4 that are required to realize the aforementioned numerical methods.     

用分子对接方法研究肝素与孕激素受体相互结合模式(英文)

用分子对接模拟软件研究了肝素与孕激素受体的相互作用。以肝素中的一糖单位作为探针对孕激素受体蛋白进行搜索,获得肝素组成单位与孕激素受体的特异性结合模式。结果发现,2-O-硫酸-α-L 艾杜糖醛酸(2-O-sulfated iduronic acid,IdoA(2S))作为肝素的核心组成单糖之一,与孕激素受体的结合能力最好。分子对接结果显示 IdoA(2S)深入到孕激素受体的 helix2 和 helix 11 所包围的结合口袋,与孕激素受体结合结构域关键残基 Asn 719 形成稳固的氢键;并与孕激素受体结合结构域的关键残基 Met 909 残基侧链近距离接触,揭示了 IdoA(2S)可能具有的孕激素受体拮抗效应的分子作用机制。本模拟实验所建立的模型能够部分解释肝素抑制孕激素依赖性乳腺癌的现象,同时推测了其相应机理。     

基于CBTC地铁隧道车-地无线信道的建模与仿真

根据隧道几何尺寸计算出无线电波在隧道中的截止频率,利用路径损耗和多径衰落进行地铁矩形隧道中无线信道的建模,对矩形隧道损耗衰落信道进行仿真,得出存在直射路径和不存在直射路径时的接收点接收信号的电平包络,仿真结果表明AP间隔距离为400 m时,接收强度大于－70 dBm,满足技术要求。     

Modeling of flux,binding and substitution of urea molecules in the urea transporter dvUT

Urea transporters (UTs) are transmembrane proteins that transport urea molecules across cell membranes and play a crucial role in urea excretion and water balance. Modeling the functional characteristics of UTs helps us understand how their structures accomplish the functions at the atomic level, and facilitates future therapeutic design targeting the UTs. This study was based on the crystal structure of Desulfovibrio vulgaris urea transporter (dvUT). To model the binding behavior of urea molecules in dvUT, we constructed a cooperative binding model. To model the substitution of urea by the urea analogue N,N′-dimethylurea (DMU) in dvUT, we calculated the occupation probability of DMU along the urea pore and the ratio of the occupation probabilities of DMU at the external (S_ext) and internal (S_int) binding sites, and we established the mutual substitution rule for binding and substitution of urea and DMU. Based on these calculations and modelings, together with the use of the Monte Carlo (MC) method, we further modeled the urea flux in dvUT, equilibrium urea binding to dvUT, and the substitution of urea by DMU in the dvUT. Our modeling results are in good agreement with the existing experimental functional data. Furthermore, the modelings have discovered the microscopic process and mechanisms of those functional characteristics. The methods and the results would help our future understanding of the underlying mechanisms of the diseases associated with impaired UT functions and rational drug design for the treatment of these diseases.     

Modeling and analysis of a hybrid communication channel based on free-space optical and radio-frequency technologies

The mathematical model of a high-speed hybrid communication system based on free-space optical (FSO) and radio-frequency (RF) technologies is considered. Multimedia information is transmitted using two communication lines operating in the hot redundancy mode, namely, an FSO channel and a millimeter radio-frequency channel. In addition, we derive ergodicity conditions for the Markov process describing the system operation and provide some performance characteristics for the hybrid communication channel.