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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.
目的 提高缓蚀剂在酸溶液中的缓蚀性能.方法 构建含有2-巯基苯并噻唑(MBT)以及不同浓度Cl–的Fe表面溶液模型,并进行分子动力学计算.观察缓蚀剂分子在Fe表面的吸附构型,考察不同Cl–值下缓蚀剂膜的致密化行为.提取缓蚀剂分子的均方位移(MSD)曲线,评价缓蚀剂膜的稳定性.计算水分子的密度分布和扩散系数,考察不同Cl–值下MBT缓蚀剂膜的驱水能力和水分子的迁移能力.结果 当Cl–值从0增加到25时,MBT膜的厚度(0.42~1.51 nm)和致密度(占有面积0.33~1.31 nm2)增加,缓蚀剂分子的自扩散系数减小(从1.25×10–9 m2/s到接近0),水分子的吸附峰强度(相对密度为72.3~33.9 nm–3)和扩散系数(1.495×10–9~0.627×10–9 m2/s)降低.当Cl–值从25增加到36时,则出现了相反的趋势.结论 缓蚀剂分子与Cl–之间存在协同作用,适当浓度的KCl可以提高MBT缓蚀剂在H2SO4溶液中的缓蚀性能.Cl–值为25时,MBT缓蚀效率最高.  相似文献   
5.
翟瑞  杨昭  张勇  吕子建  陈裕博 《化工学报》2021,72(10):5424-5429
当前环境问题日益突出,天然工质氨作为环保性制冷剂再次引起科学界的广泛重视。但NH3存在可燃可爆性问题,在实际应用中存在着一定的安全隐患。采用量子化学密度泛函理论计算方法,在M06-2X/6-311+G(d,p)的计算水平上,对NH3的燃烧及阻燃机理开展研究,得到反应过程的微观反应路径。研究表明,NH3可通过三种方式发生燃烧微观反应,一是发生自身裂解反应,生成H自由基;二是与氧气发生碰撞反应,生成OOH自由基;三是与活性自由基发生碰撞反应,生成新的活性自由基,NH3可与H、O、OH自由基反应,反应能垒较低。此外,还计算了两种典型的阻燃基团F和CF3对可燃分子NH3的微观阻燃路径,验证其阻燃效果。本文从微观分子的角度考察了可燃工质氨的燃烧及阻燃机理,为新一代低温室效应工质的燃烧及阻燃机制提供了参考。  相似文献   
6.
探讨了13X分子筛对不同初始pH的Pb(Ⅱ)溶液中Pb(Ⅱ)的吸附量、吸附速率及吸附机理,以及分子筛的碱性对溶液pH的改变。结果表明,1 g/L的13X分子筛的碱性为10^-5mol/g,Pb(Ⅱ)溶液pH为3.0~9.0时,分子筛自身的碱性会使反应溶液pH升高。当Pb(Ⅱ)溶液pH由3.0升高至12.0时,分子筛对Pb(Ⅱ)的去除率由65.1%增大至99.7%。Pb(Ⅱ)溶液pH为5.0~7.0时,13X分子筛对Pb(Ⅱ)的吸附符合拟二级动力学方程,吸附速率k_2由1.72 g/(mmol·min)增大至2.85 g/(mmol·min),而当pH达到Pb(Ⅱ)开始形成沉淀时(pH>7.0),吸附速率显著降低。13X分子筛对Pb(Ⅱ)的去除机理主要为离子交换,当溶液内开始出现Pb(Ⅱ)的沉淀时,离子交换量降低,pH=10时,离子交换量仅占总去除量的30.2%。反应过程中由于13X分子筛自身的碱性和Pb(Ⅱ)易形成羟和配离子的特性,反应体系pH会在pH<7.0形成酸性缓冲区域和8.0~10.0范围内形成碱性缓冲区域。  相似文献   
7.
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   
8.
郑振霄  戴志远  彭茜   《中国食品学报》2021,21(1):334-340
以海豹油乙酯为原料,采用尿包法和分子蒸馏法对其中的n-3PUFA进行富集,通过理化分析、气相色谱(GC)及顶空固相微萃取-气-质谱联用(HS-SPME-GC-MS)等技术研究富集过程中样品品质、脂肪酸组成和挥发性物质的变化。结果表明:尿包法和分子蒸馏法可以显著提高样品的皂化值和碘值,对酸价和过氧化物值影响不大。尿包法可以显著降低样品中饱和脂肪酸(SFA)的含量,提高n-3多不饱和脂肪酸(n-3PUFA)的含量,然而对某些长链单不饱和脂肪酸(MUFA)(C16:1,C18:1和C20:1)的分离效果有限。分子蒸馏法可有效分离SFA和MUFA,得到含量高达92.96%的n-3PUFA浓缩产物。尿包法和分子蒸馏法对样品中挥发性物质种类影响不大,而对样品中挥发性物质的含量影响显著,尿包法可显著增加样品中挥发性物质的含量,分子蒸馏则相反。其中,贡献较大的挥发性物质主要为乙醇、2-乙基己醇、十五碳烯醇、壬醛、十一醛、3,5-辛二烯-2-酮、2-壬酮、2-庚酮。  相似文献   
9.
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   
10.
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   
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