蛋白质-配体分子对接中构象搜索方法

分子对接是研究蛋白质-配体分子间相互作用与识别的有效方法。分子间的相互作用过程中形成的近天然构象是结合自由能极低的构象,快速且准确搜索能量极低的构象对于蛋白质-配体分子对接至关重要。本文回顾了蛋白质-配体分子对接中主要的构象搜索算法,包括快速穷举搜索、启发式搜索和其他搜索方法,并列举了采用不同搜索算法的代表性分子对接软件。其次,介绍了蛋白质-配体分子对接的国际评估实验、常用的测试标准库和评价的重要指标。最后,分析并指出了当前蛋白质-配体对接构象搜索方法所存在的主要问题,并对未来的工作进行了展望。     

低温流动改进剂在柴油蜡晶形成阶段的晶形控制作用

采用实验和分子动力学模拟结合的方法,考察了多种乙烯-醋酸乙烯酯(EVA)和聚甲基丙烯酸参酯(PMA)类低温流动改进剂(CFI),在蜡晶形成阶段,对蜡晶晶形的影响。结果表明,在蜡晶形成阶段,CFI通过改变柴油烃分子的排列方式和相互作用能,控制蜡晶形态,避免粒径较大且容易聚集的片状蜡晶生成。CFI分子保持伸展的构象,并对烃分子有较强的吸附能力,更利于其控制晶形作用的实现。CFI分子中的极性基团和非极性短支链可起到分散烃和分子保持聚合物分子的伸展构象的作用。CFI聚合物分子中含有较多连续的亚甲基结构有利于增强其吸附烃分子的能力。     

分子对接法预测丹皮酚及其2个异构体与β-环糊精复合物结构（英文）

β-环糊精对丹皮酚和其异构体具有明显的分子识别能力,其复合物的构象也可以极大提高其溶解能力。为了调查3个异构体和β-环糊精之间的结合模式以及相互作用,进行了分子对接和分子动力学模拟计算。采用拉马克遗传算法进行复合物可能的构象搜索,采用分子动力学评估了对接结果。对接结果分析表明3个异构体的羟基和甲氧基等的相对位置对其结合模式起到关键作用。丹皮酚(Pae)和香草乙酮(Ace)只有1个稳定的结合方式,计算结果和1H-NMR预测的一致。而2-羟基-5-甲氧基苯乙酮(Hma)和β-环糊精的可能的作用方式都不稳定。主客体之间主要的作用力为分子间氢键和疏水相互作用。分子对接法和分子动力学结合是预测β-环糊精和其配体复合物结构的1种简单方便的方法。     

分子对接模拟研究青霉素检测免疫传感器的抗体识别性能

运用"Discovery Studio软件包(version 2.1)/LigandFit模块对氨苄青霉素及其抗体的相互作用进行单分子水平的模拟研究,并对pH的影响进行探讨,以辅助研究开发经济适用的青霉素残留快速检测免疫传感器。结果表明LigandFit筛选出的相互作用构象与PDB数据库中记录的免疫复合物构象信息在结合区域、结合方式等方面可以相吻合;对于不同pH时蛋白-配体相互作用,氨苄青霉素及氨苄青霉素抗体之间的相互作用在亲和力、配体内部能量及构象间的均方根偏差(RMSD)方面具有一定差异,在模拟的条件下偏酸性条件有利于抗体与氨苄青霉素的特异性结合,以pH5.0最适。模拟结果的有效性和适用性需要进一步通过分子动力学模拟进行比较、确定,及在模拟结果的指导下进行相关试验验证。     

基于2009甲型H1N1流感病毒神经氨酸酶的分子对接研究

神经氨酸酶(NA)是流感病毒复制过程中的关键酶,基于NA结构设计的抑制剂(NAI)已成为临床上最主要的抗流感病毒药物。由于2009甲型H1N1流感病毒NA(09N1)与以往NA亚型的三维结构不同,对09N1的深入研究可为新型NAI的设计打开思路。本文利用分子对接软件GOLD和Surflex-Dock对09N1-NAI复合物(09N1体系)进行对接研究,采用配体对接构象的RMSD值和KISS score值(复合物晶体结构中氢键作用的重现率)等两项指标评价分子对接效果,并进一步分析NAI与09N1之间的相互作用。结果:所有配体得分最高构象的RMSD值均小于2.0 A,且KISS score值均较高,在GOLD对接中,基于打分函数GoldScore的对接结果优于ChemScore.氢键作用、静电作用、疏水作用和范德华力在配体对接构象得分中均占一定比例。结论;GOLD和Surflex-Dock对09N1体系的分子对接均具有一定可靠性,在GOLD对接中宜选GoldScore作为打分函数;通过对接验证了氢键作用、静电作用和疏水作用在NAI与NA结合中的重要性,提出范德华力对分子间的相互作用也有重要贡献。     

纳米增强酶生物传感器原理研究取得重要进展

6月，由中科院理化技术研究所主持的国家自然科学基金项目“酶分子构象影响传感器信息传递原理研究”通过评审组专家评审，并被确定为“特优项目”。该研究从分子水平上探索了纳米材料与生物分子的结合和相互作用，从而指导分子生物传感器的组装应用，涉及当今生物分子传感技术研究的重大方向与前沿领域，它的突破将为研究组装发展有实用意义的生物功能信息处理原型器件提供新的广阔前景。     

VEGF-B与去甲斑蝥素相互作用的分子动力学研究

利用分子对接(Molecular docking)结合分子动力学(Molecular dynamics,MD)模拟方法,建立去甲斑蝥素(Norcantharidin,NCTD)与血管内皮生长因子B(Vascular endothelial growth factor B,VEGF-B)的相互作用模型,分析二者的结合方式,结合能力,探究NCTD与VEGF-B的相互作用机制。结果表明,分子对接生成稳定的NCTD/VEGF-B复合物,NCTD与VEGF-B蛋白主链的Tyr117,Cys156,Gln46形成了氢键。经4ns的MD模拟后,NCTD/VEGF-B复合物体系达到了平衡,分析动力学轨迹并计算结合自由能证明了NCTD与VEGF-B的结合稳定合理。氢键、静电作用和疏水性为NCTD与VEGF-B稳定结合的主要贡献。本工作模建结果对开展NCTD抑制VEGF-B活性来控制肿瘤发生具有一定的理论意义。     

真空条件下扑热息痛的α-环糊精包合物的分子动力学模拟

真空状态下,扑热息痛药物分子(客体)和α-环糊精(主体)形成的包合物,在一定时间内动态微观结构分子动力学模拟的研究结果表明:扑热息痛分子可以通过两端亲水,中间疏水的三重作用,与α-环糊精形成稳定包合形式,由于空穴狭小,致扑热息痛分子的运动大受限制;计算结果表明:扑热息痛和α-环糊精包合后势能明显下降,原因为两者之间的范德华相互作用和氢键作用。本文还给出了主客体包合物的时间平均构象。最后,分子动力学模拟结果,通过UV光谱和理论UV光谱实验的对比得到了验证。     

一种基于免疫遗传算法的分子对接构象搜索策略

分子对接是计算机辅助药物分子优化设计中的一种重要方法,搜索算法和评分函数是当前分子对接研究的难点与热点.在借鉴当前分子对接构象搜索策略的基础上,提出了一个基于免疫遗传算法的分子对接药物设计方法AutoDockIGA.首先建立了基于最优化方法的分子对接数学模型AutoDockModel,并设计了基于免疫遗传算法的构象搜索策略,运用此方法对布克海文蛋白质数据库中(Brookhaven Protein Data Bank)的6种蛋白质一配体复合物进行了实验测试,并将实验结果与AutoDock3.0、模拟退火算法的对接时间和精度进行比较和分析,实例测试表明AutoDockIGA具有更高的寻优能力.     

苯胺取代白叶藤碱衍生物与双链DNA相互作用的光谱及分子对接研究

运用紫外吸收光谱法研究了苯胺取代白叶藤碱衍生物与小牛胸腺DNA的结合作用:光谱实验结果表明,衍生物可能是以嵌插方式与小牛胸腺DNA结合。并运用Surflex-dock方法对衍生物与双链DNA的相互作用进行了分子对接研究,分析了小分子和受体的结合模式:对接结果表明,化合物插入到双螺旋DNA的碱基对中间,化合物与双链DNA的主要通过π-π堆积作用来相互结合。紫外实验和分子对接理论研究结果一致,两者相互补充,能够从实验和理论两方面协同研究药物分子与DNA之间的相互作用。     

面向血管疾病诊断及预测分析的血流动力学模拟综述

目的血流动力学模拟方法对于揭示动脉瘤、动脉粥样硬化斑块等血管疾病的形成、发展和破裂的病理形成机制、诊断及术后评估具有重要研究意义,已经成为血管疾病诊断与预测分析临床应用与研究领域的一个热点方向。方法根据血流动力学模拟过程中模拟的血流的特征尺度的不同,本文采用宏观尺度血流动力学模拟和多尺度血流动力学模拟的两种分类方法进行综述。结果总结了不同特征尺度模拟情况下的血流动力学模拟与分析方法的国内外研究现状、主要研究方法和关键技术,并阐述了其中存在的研究难点,展望了血流动力学模拟未来的研究发展方向。结论随着当前血管疾病患者人数的日益增长,结合基于图像信息的血管建模技术和人体生理真实性血流信息的多尺度血流动力学模拟方法的研究将成为该领域一个新的研究热点,对于提高我国血管疾病治疗水平具有重要研究意义。     

Hydrokinetic approach to large-scale cardiovascular blood flow

We present a computational method for commodity hardware-based clinical cardiovascular diagnosis based on accurate simulation of cardiovascular blood flow. Our approach leverages the flexibility of the Lattice Boltzmann method to implementation on high-performance, commodity hardware, such as Graphical Processing Units. We developed the procedure for the analysis of real-life cardiovascular blood flow case studies, namely, anatomic data acquisition, geometry and mesh generation, flow simulation and data analysis and visualization. We demonstrate the usefulness of our computational tool through a set of large-scale simulations of the flow patterns associated with the arterial tree of a patient which involves two hundred million computational cells. The simulations show evidence of a very rich and heterogeneous endothelial shear stress pattern (ESS), a quantity of recognized key relevance to the localization and progression of major cardiovascular diseases, such as atherosclerosis, and set the stage for future studies involving pulsatile flows.     

面向血液循环系统仿真的全身血管重建

血管的点云数据表示在医疗中有着重要的作用,可以帮助医护人员直观地了解血管的几何信息.对于医疗辅助技术、放射学模拟等应用中,除了对局部的血管系统几何信息进行可视之外,也需要对全身血管进行准确的仿真建模,从而对整体血管系统的拓扑及几何信息都需要进行系统性的重建.传统骨架提取技术无法保证血管模型正确的连接拓扑,提出了一种基于点云数据的交互式全身血管模型重建方法,通过对血管数据分段和拟合,并分析各段血管端点连接情况,重建了一种带有血管截面半径信息的全身血管一维骨架模型,且该模型能直接用于血流血压等仿真.与已有方法相比,其优势在于能应用于大规模的复杂的全身血管点云数据,且重建的模型可以直接用于仿真.BodyParts3D数据集下实验结果表明,与已有方法相比,文中方法重建的全身血管一维骨架模型具有准确的拓扑连接,能够生成更好的仿真效果.     

心血管系统仿真模型的研究

为了深入研究心血管系统的生理机制以及探讨心血管系统的血流动力学参数与心血管疾病之间的关系,文中基于流体力学与电气网络的相关基础理论,根据人体心血管循环系统的解剖模型,提出一种基于集总参数的由体循环、肺循环和心脏组成的心血管系统仿真模型。重点分析了体循环子模型,并利用MATLAB 工具进行数学仿真,得出正常生理状况下的心血管参数,给出收缩压、舒张压、心室血容量等血流动力学参数。根据临床诊断参数调整体循环模型的各个参数,利用计算机仿真出高血压和心衰状况下的血流动力学仿真结果。仿真结果与临床的症状相一致,证明文中提出的模型具有一定的可行性。     

Equivalent electrical network for performance characterization of piezoelectric peristaltic micropump

Utilizing an electronic–hydraulic analogy, this study develops an equivalent electrical network of a piezoelectric peristaltic micropump which has not been modeled the whole system operation completely by computational fluid dynamics (CFD) or equivalent electrical network so far due to its excessive complicated structure. The validity of the proposed model is verified by comparing the simulation results obtained using the SPICE (simulation program with integrated circuit emphasis) software package for flow rate spectrum and its maximum state of a typical micropump with the experimental observations for two working fluids, namely DI water and blood. The simulation results predict a maximum flow rate frequency and flow rate of 280 Hz and 43.23 μL/min, respectively, for water, and 210 Hz and 24.12 μL/min for blood. The corresponding experimental results are found to be 300 Hz and 41.58 μL/min for water and 250 Hz and 23.75 μL/min for blood. The relatively poorer agreement between the two sets of results when using blood as the working fluid is thought to be the result of the non-Newtonian nature of blood, which induces a more complex, non-linear flow behavior within the micropump. Having validated the proposed model, the equivalent network is used to perform a systematic analysis of the correlation between the principal micropump design parameters and operating conditions and the micropump performance. The results confirm the validity of the equivalent electrical network model as the first microfluidic modeling tool for optimizing the design of peristaltic micropumps and for predicting their performance.     

High resolution turbulence modelling of airflow in an idealised human extra-thoracic airway

Computational fluid dynamic (CFD) studies of the flow inside a modelled human extra-thoracic airway (ETA) were conducted to evaluate the performance of several turbulence models in predicting flow inside this complex geometry. Veracity of the computational models is assessed for physiologically accurate flow rates of 10, 15, and 30 l/min by comparison of numerical results with hot-wire [Johnstone A, Uddin M, Pollard A, Heenan A, Finlay WH. The flow inside an idealised form of the human extra-thoracic airway. Exp Fluids 2004;37(5):673-89] and particle image velocimetry (PIV) [Heenan AF, Matida E, Pollard A, Finlay WH. Experimental measurements and computational modelling of the flow field in an idealised extra-thoracic airway. Exp Fluids 2003;35:70-84] mean velocity data for the central sagittal plane of the ETA. Furthermore, flow features predicted by numerical models are compared to those from experimental flow-visualisation studies [Johnstone et al., 2004]. The flow in the ETA is shown to be highly three-dimensional, having strong secondary flows.     

Studying the influence of gravitational overloads on the parameters of blood flow in vessels of greater circulation

The paper is devoted to the numerical modeling of the blood flow in the human cardiovascular system with allowance for gravitational action. A model of the operation of the heart and an equation of state are proposed and studied. Modifications of the graph of the cardiovascular system for the simulation of possible positions of the object in conditions of multifold gravitational overloads are considered.     

Generation and Visual Exploration of Medical Flow Data: Survey,Research Trends and Future Challenges

Simulations and measurements of blood and airflow inside the human circulatory and respiratory system play an increasingly important role in personalized medicine for prevention, diagnosis and treatment of diseases. This survey focuses on three main application areas. (1) Computational fluid dynamics (CFD) simulations of blood flow in cerebral aneurysms assist in predicting the outcome of this pathologic process and of therapeutic interventions. (2) CFD simulations of nasal airflow allow for investigating the effects of obstructions and deformities and provide therapy decision support. (3) 4D phase‐contrast (4D PC) magnetic resonance imaging of aortic haemodynamics supports the diagnosis of various vascular and valve pathologies as well as their treatment. An investigation of the complex and often dynamic simulation and measurement data requires the coupling of sophisticated visualization, interaction and data analysis techniques. In this paper, we survey the large body of work that has been conducted within this realm. We extend previous surveys by incorporating nasal airflow, addressing the joint investigation of blood flow and vessel wall properties and providing a more fine‐granular taxonomy of the existing techniques. From the survey, we extract major research trends and identify open problems and future challenges. The survey is intended for researchers interested in medical flow but also more general, in the combined visualization of physiology and anatomy, the extraction of features from flow field data and feature‐based visualization, the visual comparison of different simulation results and the interactive visual analysis of the flow field and derived characteristics.     

A systematic methodology for large scale compound screening: A case study on the discovery of novel S1PL inhibitors

Decrease in sphingosine 1-phosphate (S1P) concentration induces migration of pathogenic T cells to the blood stream, disrupts the CNS and it is implicated in multiple sclerosis (MS), a progressive inflammatory disorder of the central nervous system (CNS), and Alzheimer’s disease (AD). A promising treatment alternative for MS and AD is inhibition of the activity of the microsomal enzyme sphingosine 1-phosphate lyase (S1PL), which degrades intracellular S1P. This report describes an integrated systematic approach comprising virtual screening, molecular docking, substructure search and molecular dynamics simulation to discover novel S1PL inhibitors. Virtual screening of the ZINC database via ligand-based and structure-based pharmacophore models yielded 10000 hits. After molecular docking, common substructures of the top ranking hits were identified. The ligand binding poses were optimized by induced fit docking. MD simulations were performed on the complex structures to determine the stability of the S1PL-ligand complex and to calculate the binding free energy. Selectivity of the selected molecules was examined by docking them to hERG and cytochrome P450 receptors. As a final outcome, 15 compounds from different chemotypes were proposed as potential S1PL inhibitors. These molecules may guide future medicinal chemistry efforts in the discovery of new compounds against the destructive action of pathogenic T cells.     

The influence of size, shape and vessel geometry on nanoparticle distribution

Nanoparticles (NPs) are emerging as promising carrier platforms for targeted drug delivery and imaging probes. To evaluate the delivery efficiency, it is important to predict the distribution of NPs within blood vessels. NP size, shape and vessel geometry are believed to influence its biodistribution in circulation. Whereas, the effect of size on nanoparticle distribution has been extensively studied, little is known about the shape and vessel geometry effect. This paper describes a computational model for NP transport and distribution in a mimetic branched blood vessel using combined NP Brownian dynamics and continuum fluid mechanics approaches. The simulation results indicate that NPs with smaller size and rod shape have higher binding capabilities as a result of smaller drag force and larger contact area. The binding dynamics of rod-shaped NPs is found to be dependent on their initial contact points and orientations to the wall. Higher concentration of NPs is observed in the bifurcation area compared to the straight section of the branched vessel. Moreover, it is found that Péclet number plays an important role in determining the fraction of NPs deposited in the branched region and the straight section. Simulation results also indicate that NP binding decreases with increased shear rate. Dynamic NP re-distribution from low to high shear rates is observed due to the non-uniform shear stress distribution over the branched channel. This study would provide valuable information for NP distribution in a complex vascular network.