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1.
The calcium pump (sarco/endoplasmic reticulum Ca2+-ATPase, SERCA) plays a major role in calcium homeostasis in muscle cells by clearing cytosolic Ca2+ during muscle relaxation. Active Ca2+ transport by SERCA involves the structural transition from a low-Ca2+ affinity E2 state toward a high-Ca2+ affinity E1 state of the pump. This structural transition is accompanied by the countertransport of protons to stabilize the negative charge and maintain the structural integrity of the transport sites and partially compensate for the positive charges of the two Ca2+ ions passing through the membrane. X-ray crystallography studies have suggested that a hydrated pore located at the C-terminal domain of SERCA serves as a conduit for proton countertransport, but the existence and function of this pathway have not yet been fully characterized. We used atomistic simulations to demonstrate that in the protonated E2 state and the absence of initially bound water molecules, the C-terminal pore becomes hydrated in the nanosecond timescale. Hydration of the C-terminal pore is accompanied by the formation of water wires that connect the transport sites with the cytosol. Water wires are known as ubiquitous proton-transport devices in biological systems, thus supporting the notion that the C-terminal domain serves as a conduit for proton release. Additional simulations showed that the release of a single proton from the transport sites induces bending of transmembrane helix M5 and the interaction between residues Arg762 and Ser915. These structural changes create a physical barrier against full hydration of the pore and prevent the formation of hydrogen-bonded water wires once proton transport has occurred through this pore. Together, these findings support the notion that the C-terminal proton release pathway is a functional element of SERCA and also provide a mechanistic model for its operation in the catalytic cycle of the pump.  相似文献   
2.
Heparanase (Hpse) is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains. Its upregulated expression is implicated in tumor growth, metastasis and angiogenesis, thus making it an attractive target in cancer therapeutics. Currently, a few small molecule inhibitors have been reported to inhibit Hpse, with promising oral administration and pharmacokinetic (PK) properties. In the present study, a ligand-based pharmacophore model was generated from a dataset of well-known active small molecule Hpse inhibitors which were observed to display favorable PK properties. The compounds from the InterBioScreen database of natural (69,034) and synthetic (195,469) molecules were first filtered for their drug-likeness and the pharmacophore model was used to screen the drug-like database. The compounds acquired from screening were subjected to molecular docking with Heparanase, where two molecules used in pharmacophore generation were used as reference. From the docking analysis, 33 compounds displayed higher docking scores than the reference and favorable interactions with the catalytic residues. Complex interactions were further evaluated by molecular dynamics simulations to assess their stability over a period of 50 ns. Furthermore, the binding free energies of the 33 compounds revealed 2 natural and 2 synthetic compounds, with better binding affinities than reference molecules, and were, therefore, deemed as hits. The hit compounds presented from this in silico investigation could act as potent Heparanase inhibitors and further serve as lead scaffolds to develop compounds targeting Heparanase upregulation in cancer.  相似文献   
3.
Chameleonic properties, i. e., the capacity of a molecule to hide polarity in non-polar environments and expose it in water, help achieving sufficient permeability and solubility for drug molecules with high MW. We present models of experimental measures of polarity for a set of 24 FDA approved drugs (MW 405-1113) and one PROTAC (MW 1034). Conformational ensembles in aqueous and non-polar environments were generated using molecular dynamics. A linear regression model that predicts chromatographic apparent polarity (EPSA) with a mean unsigned error of 10 Å2 was derived based on separate terms for donor, acceptor, and total molecular SASA. A good correlation (R2=0.92) with an experimental measure of hydrogen bond donor potential, Δlog Poct-tol, was found for the mean hydrogen bond donor SASA of the conformational ensemble scaled with Abraham's A hydrogen bond acidity. Two quantitative measures of chameleonic behaviour, the chameleonic efficiency indices, are introduced. We envision that the methods presented herein will be useful to triage designed molecules and prioritize those with the best chance of achieving acceptable permeability and solubility.  相似文献   
4.
分别从热力学和动力学方面研究了低碳含钛微合金钢凝固过程选分结晶对TiN夹杂物析出的影响。热力学分析表明,液相线温度以上不会有TiN析出;由于凝固过程凝固前沿Ti、N元素富集,凝固分数达到0.377时,凝固前沿固相中开始析出TiN;凝固末期,Ti和N的富集程度进一步增大,固液相中均有TiN析出。动力学分析表明,随着冷却速度的降低,凝固过程TiN夹杂物的尺寸显著增加,当冷速高于50 K/s时,TiN的理论半径为5.5 μm,当冷速低于5 K/s时,TiN的理论半径在17.5 μm以上;固相中析出的TiN为纳米级别。铸坯中TiN析出物主要尺寸为1~5 μm,且大尺寸夹杂主要在铸坯厚度方向的1/4处和中心处析出,这表明铸坯中的大尺寸夹杂物是在凝固过程中析出的。  相似文献   
5.
使用马来酸酐(MA)、乙酸乙烯酯(VA)、乙烯基磺酸钠(VS)和2-丙烯酰胺-2-甲基丙磺酸(AMPS)合成了一种四元共聚物阻垢剂MA-VA-VS-AMPS,并探究其在高Ca2+质量浓度和高矿化度环境中的阻垢机理。采用FT-IR分析阻垢剂结构,研究了阻垢剂质量浓度、Ca2+质量浓度、溶液温度和pH值等因素在静态条件下对阻垢剂阻垢性能的影响;利用动态流动测试方法评价阻垢剂在动态条件下的阻垢率;采用Materials studio(MS)中分子动力学模拟方法计算阻垢剂与CaCO3之间的结合能;采用扫描电镜(SEM)和X-射线衍射(XRD)仪分析CaCO3晶体的形貌和晶型。结果表明:在静态测试条件下,MA-VA-VS-AMPS的阻垢率是99.3%;在动态测试条件下,MA-VA-VS-AMPS的阻垢率为96.8%,且阻垢剂使CaCO3发生变形, Ca2+和阻垢剂中的O之间形成了化学键,阻垢剂与CaCO3发生吸附作用。  相似文献   
6.
针对DZLY180型硬齿面点线啮合齿轮减速器,利用SolidWorks建立其高速级齿轮副三维模型,采用Ansys Workbench对模型进行动态接触应力仿真分析,然后对其进行修形并重新建模、仿真,结果显示修形后点线啮合齿轮接触应力减小,啮入冲击得到明显改善。  相似文献   
7.
The anoctamin (TMEM16) family of transmembrane protein consists of ten members in vertebrates, which act as Ca2+-dependent ion channels and/or Ca2+-dependent scramblases. ANO4 which is primarily expressed in the CNS and certain endocrine glands, has been associated with various neuronal disorders. Therefore, we focused our study on prioritizing missense mutations that are assumed to alter the structure and stability of ANO4 protein. We employed a wide array of evolution and structure based in silico prediction methods to identify potentially deleterious missense mutations in the ANO4 gene. Identified pathogenic mutations were then mapped to the modeled human ANO4 structure and the effects of missense mutations were studied on the atomic level using molecular dynamics simulations. Our data show that the G80A and A500T mutations significantly alter the stability of the mutant proteins, thus providing new perspective on the role of missense mutations in ANO4 gene. Results obtained in this study may help to identify disease associated mutations which affect ANO4 protein structure and function and might facilitate future functional characterization of ANO4.  相似文献   
8.
Li metal anode is the “Holy Grail” material of advanced Lithium-ion-batteries (LIBs). However, it is plagued by uncontrollable dendrite growth resulting in poor cycling efficiency and short-circuiting of batteries. This has spurred a plethora of research to understand the underlying mechanism of dendrite formation. While experimental studies suggest that there are complex physical and chemical interactions between heterogeneous solid-electrolyte interphase (SEI) and dendrite growth, most of the studies do not reveal the mechanisms triggering these interactions. To deal with this knowledge gap, we propose a multiscale modeling framework which couples kinetic Monte Carlo and Molecular Dynamics simulations. Specifically, the model has been developed to account for (a) heterogeneous SEI, (b) dendrite-SEI interactions, and (c) effect of electrolyte on Li electrodeposition and potential dendrite formation. This allows the proposed computational model to be extended to various electrolytes and SEI species and generate results consistent with previous experimental studies.  相似文献   
9.
The design of a liquid/liquid contact apparatus necessitates the knowledge of fluid dynamics and mass transfer in the dispersion. Prediction of process parameters is challenging due to swarm and interfacial effects. Single drop investigations are suitable to enable a sophisticated dimensioning based on few simple experiments combined with published theories and correlations. In the first part of this article, the fundamentals of fluid dynamics and mass transfer in absence of interfacial effects were explained. Here, an overview of relevant interfacial phenomena and the influence of different substances typically occurring in technical applications as impurities or accompanying components is given.  相似文献   
10.
The weeping phenomenon was investigated using some experimental tests and a numerical model. The tests were performed within a 1.22‐m‐diameter pilot‐scale column including two chimney trays and two Nye test trays with an air‐water system. The rates of weeping were measured in the Nye trays with two heights of the weir and a hole area of 5 %. Moreover, the weeping rates in the outlet and inlet halves of the Nye tray and the total weeping rate were calculated. In the next step, an Eulerian‐Eulerian computational fluid dynamics (CFD) technique was used. The results show good agreement between the attained CFD findings and the experimental data.  相似文献   
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