Discovery Studio 讲义中文

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Discovery Studio 讲义

Appendix : Preparing a PDB File for Use as a HomologyModeling TemplateThe basic principle of homology modeling is that you map the sequence of an unknown protein onto the structure of a known protein. Thus, if you do not have the known protein, or the template, you will not be able to build the model. A common source for templates is the Protein Data Bank at the Research Collaboratory for Structural Bioinformatics (RCSB). The website for the RCSB is /.The Protein Data Bank (PDB) is possibly the world’s leading public source of three-dimensional data for biological molecules (1). As of July 2006, over 37,000 entries could be found in the PDB. Hundreds more are being added every month. Both X-ray diffraction and other solid-state techniques account for the majority of the structures. However, over 5500 NMR structures are also available. These deposited structures include proteins, peptides, nucleic acids, carbohydrates, and complexes of these molecules.Preparation of these molecules for work in the Discovery Studio environment is a critical process to your modeling efforts. This exercise examines how to prepare a PDB file as a template for a homology modeling project. You will learn in the lesson how to:•Load a PDB file directly from the Protein Data Bank,•Produce and examine the Protein Report,•Remove the crystallographic unit cell,•Split the molecule,•Delete unneeded components, and•Save the completed file.1. Start Discovery StudioWe must have Discovery Studio running to start the exercise.Launch the Discovery Studio client if it not already running.If Discovery Studio is already running, from the Windows menu, select the Close All command. If you are prompted to save any molecules or data, select No.2. Load the PDB fileNow, we will load the PDB file directly from the RCSB through the Discovery Studio interface. Note: The File | Open URL… command only will obtain files through a network connection to a PDB server. An error is returned if the connection is not possible. Check with your instructor or system administrator if a connection is available from your workshop location.From the File pulldown menu, select the Open URL… command. In the dialog box, the URL should refer to the RCSB site. Replace the last four characters of the URL with 1T64.Click the Open button.If a connection to the PDB cannot be made, the required file is available in the DataFiles directory as 1T64_original.pdb.The structure displayed in the 3D Window is the crystal structure of two human HDAC8 proteins in complex with an inhibitor, 684 crystallographic waters, and several ions. The inhibitor is trichostatin A, a well-studied inhibitor of histone deacetylases (2).From the View menu, select the Hierarchy command.Note the distribution of components in the Hierarchy View. We will rearrange the components to facilitate working with the structure.3. Examine the Protein ReportBefore delving into the protein, we should take a moment to see what is there. A quick way of accomplishing this task is to use the Protein Report.In the Protein Reports and Utilities Tool Panel, go to the Protein Information section and click the Protein Report command.This will open an HTML Window with a text document summarizing key information about the 1T64 protein structure. As we have more than one molecule in the view, the report begins with a list of the molecules.Scrolling down the report you will notice that first there are two chains, A and B.Also, there are alternative conformations and missing residues for both chains. There are more problematic residues in the A chain than in the B chain.Scrolling further down you will see that there are several ligands and ions included in the structure as well as the crystallographic waters.Based upon the data reported, we could conclude that the B chain is a better template than the A chain. But we will need to clear our several nonprotein atoms as well.4. Remove the unit cellThe crystallographic unit cell often has little meaning in molecular mechanics calculations. Sometimes it is just easier to remove the unit cell.From the Structure menu, select the Crystal Cell pullright menu. Choose the Remove Cell command.Note the change in the Hierarchy View as the unit cell information is removed.Expand the object 1T64 to verify that the protein and water molecules are still present.5. Split the components of the molecular systemThis PDB file is composed of many parts. We can view the components through the Hierarchy Window explored in other exercises. However, we can actually separate the components of the PDB file quicker with the Split command.Access the Tools Explorer. Then access the Protein Reports and Utilities tools.Find the Split tool group. Three options are listed and will be described in a moment.Click the All command.Note the change in the Hierarchy View. The four components of the PDB file have beensegregated into separate objects and renamed.The four components are the protein (1t64_A and 1t64_B), the ligand (1t64_NonProtein), and the crystallographic water (1t64_Water).The three options for the Split command allow some flexibility in how to manipulate objects.All Splits out all chains and non-protein substructures into separate objects in the Hierarchy View and lists each amino acid sequence as a separate sequence in the Sequence View.Protein Splits out all protein chain substructures into separate objects in the Hierarchy View and lists each amino acid sequence as a separate sequence in the Sequence View.Non-Protein Splits out ligands and other non-protein substructures such as waters into separate objects in the Hierarchy View and lists any non-protein polypeptide sequences as separate sequences in the Sequence View.6. Remove the waterFor this exercise, we will remove the crystallographic water molecules. There are several ways that the waters could be removed. In this case, as we split the system and developed a new hierarchy, we will use the Hierarchy View.In the Hierarchy View, select the entry 1t64_Water. The entry should be selected in both the Hierarchy View and the 3D Window.Click the Delete key on the keyboard.The water molecules are removed from both the Hierarchy View and the 3D Window.7. Remove the ligand and ionsNeither the ligand nor the ions are required for our homology modeling experiment. So we may remove them.In the Hierarchy View, select the entry 1t64_NonProtein.Click the Delete key on the keyboard.The ligand and ions molecules are removed from both the Hierarchy View and the 3D Window.8. Remove one of the protein unitsTwo protein chains are shown in this unit cell. However, only one will be needed as a template. Which one to keep will be dependent upon the quality of the individual chains. In this case, we saw in the Protein Report that chain A has more residues with problems (missing atoms and alternate conformations) than chain B. Therefore, we will retain only the B chain.In the Hierarchy View, select the entry 1t64_A.Click the Delete key on the keyboard.Only the B chain remains visible.9. Clean the proteinDiscovery Studio can automate many of the tasks required to properly prepare a protein for an energy calculation. Before performing the clean operation, we can specify what operations to conduct through the Preferences dialog.From the Edit menu, select the Preferences… command.In the Preferences dialog, expand the Protein Utilities page. Select the Clean Protein page.At this point, we have several options that can be set. These options will address common problems that may be present in PDB files. For example, X-ray crystal structures will typically not have hydrogen atoms, so these must be added. Also, the chain ends must be set with the correct chemistry and any missing atoms in residues must be placed. The options are described below.NonStandard Names Checks whether atom names conform to the standardnames and corrects them if necessary.Disorder (Retain One Set) Checks for disordered atoms and retains only the first set.CorrectProblemsIncomplete Residues Adds missing side chain atoms to amino acids. Thisoperation will not fill in missing loop regions.Desired pH Allows the protonation state of the ionizable amino acids and the termini to be controlled using the standard pK a values. The protonation state is adjusted after any modifications of the hydrogens and termini by the following options.Hydrogens If the Modify Hydrogensoption is checked,hydrogens will be addedas needed.All Hydrogens: All hydrogen atoms are added.Polar Hydrogens: Only those hydrogen atoms thatcould be involved in hydrogen bonds will be added.No Hydrogens: No hydrogen atoms are added.Termini If the Modify Termini option is checked, then termini will be added or removed as indicated.Fix Connectivity and Bond Orders Ensures that amino acids have the correct bond order. This option will have no effect on nonstandard amino acids or ligands.We will set the Clean Protein preferences now.Turn on preferences as shown in Figure 1 (on the next page). Click the OK button in the Preferences dialog and return to the 3D window.Now, we may actually clean the protein.In the Hierarchy View, select the entry 1t64_A.Access the Tools Explorer. Then access the Protein Reports and Utilities tools.Click the Clean command.After a few moments, the protein structure that is present in the 3D Window changes. Most notably hydrogen atoms are now added to the structure. Other operations have also been performed also such as completing a missing residues and correcting atom names.10. Saving the new complexWe will save this protein for later use. Ensure the 3D Window is active.Click the Fit to Screen button.From the File pulldown menu, select the Save As… command.For Object Name enter the name 1T64. Ensure the File of type: parameter is set toViewer (*.msv).Click the Save button.11. Complete the lessonClose all the windows in Discovery Studio.From the Window menu, select the Close All command.Alternatively, you could simply exit Discovery Studio.Figure 1: Clean Protein preferences panelIf asked to save any data, select No.With this lesson, we have taken a PDB file composed of various molecular entities. We have broken apart these molecular components and regrouped them as needed. Then we saved the structure. With homology modeling using Discovery Studio, we do need to be as rigorous as we do when performing an energy calculation. Thus, it is not even necessary to type the molecule – just so long as we do not do an energy calculation. Homology modeling only needs a valid protein structure as a template, and that is what we have made here.References:1. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, et al. 2000. The Protein DataBank. Nucleic Acids Res 28: 2352. Yoshida M, Kijima M, Akita M, Beppu T. 1990. Potent and specific inhibition ofmammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem 265: 17174Hands-On Exercises: Sequence SearchingLesson 1: BLAST SearchesThe acetylation at the ε-amino group of specific lysines in histones play a crucial role in transcription and gene regulation (11). The removal of the acetyl group is accomplished through, histone deacetylases (HDACs) which deactylate histones in nucleosomes. Recently, inhibitors of histone deacetylases have been identified to induce growth arrest, differentiation, and apoptotic cell death of cancerous cells (9), thus having some pharmaceutical potential. However, there are several classes of HDACs; and, each has a distinct role in gene expression (7). Developing class specific inhibitors of HDACs is a strategy being employed for the development of anticancer drugs.To aid in designing these specific inhibitors, the structures of the different target HDACs will be needed. However, rather than waiting for crystal structures, work has been underway to create homology models of HDACs (15). In the study from Wang and co-workers, homology models were built for four class I histone deacetylases to investigate binding modes of inhibitors. We use that work as a basis for exercises in this workshop.Before beginning any homology modeling experiment, it is imperative that you have a homologous protein upon which to build your model. Discovery Studio offers access to BLAST and PSI-BLAST searches of protein sequence databases. BLAST searches are used to identify close homologues of the target sequence (1). Gapped BLAST and PSI-BLAST searches are useful for identifying more distant homologues (2).In this tutorial, you will run a BLAST search with a sequence of a human histone deacetylase (HDAC1) to find homologous sequences in the PDB database. We will use the hits to help determine a suitable template to build a homology model of HDAC1.After completing this lesson, you will be familiar with:•Reading a sequence into Discovery Studio from an external source,•Using the BLAST protocol for performing a search, and•Loading and analyzing the hits obtained.1. Obtain the target sequenceNote: Check with you instructor if an Internet connection and a browser are available at your training site. If not, a prepared file is available for the exercise.We will start by obtaining the sequence of our target or the unknown structure.Start your Internet browser on your computer.Enter the URL /Database/ to go to the NCBI database.In the Search box, change Entrez to Protein.Then enter the Genbank accession number Q13547. Click Go to conduct the search.You will see an entry for human histone deacetylase HDAC1 (14). The entry is in a format that cannot be loaded into Discovery Studio. We must change the format.Change the Display setting to FASTA.The sequence of the HDAC is now displayed in a FASTA or Pearson format (12) that can be read by Discovery Studio. The FASTA format is a simple ASCII text file commonly used for transferring sequences. But, we need to get the sequence into a file for importing.Next to the Display setting is a pulldown menu marked Send to. Change the Send to parameter to File.The next step is dependent upon your specific browser and settings. Thus, the instructions are rather general.A dialog box should appear asking what you want to do with the file. Select Save. If prompted for a file name, enter sequences.fasta. If prompted for a location, choose Desktop. Save the file.The file will be saved on your Desktop. If you have trouble locating or downloading the file, do not be concerned. The sequence is available in the workshop data files, usually in the DataFiles folder on the Desktop.Also, there are a myriad of places where we could have obtained the sequence. For example, we could have used Accelrys GCG (commonly known as the Wisconsin Package) and searched the databases there. Or we could have gone to other databases available on the Internet such as SWISS-PROT (URL /sprot/). Wherever we obtain the sequence it must be obtained in a file format readable by Discovery Studio. The list of suitable formats was presented in the lecture.2. Start Discovery StudioWe must have Discovery Studio running to start the exercise.Launch the Discovery Studio client if it not already running.If Discovery Studio is already running, from the Window menu, select the Close All command. If you are prompted to save any molecules or data, select No.3. Load the HDAC1 sequenceWe will load a sequence file of the human histone deacteylase.From the File pulldown, select the Open… command.In the Files of type: pulldown, select Sequence Formats to filter out non-sequence files.Click the Desktop icon to jump to the Desktop. Select the sequence file you just downloaded, sequences.fasta or whatever you have named the file. If you are unable to locate the file, you can browse to the Desktop/DataFiles directory and use the file HDAC1.fasta.Click the Open button.The Sequence Window will appear presenting the amino acid sequence of our unknown. Discovery Studio gives the sequence a name derived from the NCBI index number. We will rename it to something more understandable.In the Sequence Window, double-click on the sequence or the name of the sequence. Ensure the entire sequence is highlighted.Right click and choose the Rename Sequence… command. In the dialog that opens enter the name HDAC1. Click OK. Deselect everything.3. Run a BLAST searchYou access the BLAST program through the protocols.From the Protocol Explorer, open the Protein Modeling protocol group.Select the BLAST protocol.The parameter explorer will appear with settings available for a BLAST search.For the Sequence parameter, enter the sequence window and name sequences:HDAC1.In a similar manner as specifying structures, the specific sequence is appended to the name of the sequence window. You may only select one sequence at a time to use in the search.Ensure the Database parameter is set to PDB_nr95.The default database is a high quality, non-redundant set derived from the PDB (3). Other supported databases are nrdb from NCBI, nrdb90 from EBI, PDB, and Swiss-Prot as described in the lecture. If you add a new BLAST formatted database to the database directory, it is also listed.Ensure the Matrix parameter is set to BLOSUM62.You have the options to use the BLOSUM (6) or PAM (4) matrices. The BLOSUM62 matrix is a reasonable start in most searches.Ensure the Gapped Alignment is set to True.This option allows you to select whether the calculation is carried out using a gapped BLAST or BLAST searches can be run. Gapped BLAST is the equivalent of one iteration of PSI-BLAST (2).We will leave the remaining options set to their default values as below:Gap costs Existence: 11 Extension: 1Expectation Value10Filter Low complexity TrueNumber of Sequences in Output250These four parameters allow you to specify how the search will be continued. It is beyond the scope of this workshop to explain all the options possible. A more through discussion of BLAST searches is available in the Accelrys GCG Workshop. BLAST options are also thoroughly discussed in a recent book (8).Click the Run button.The run will start and complete in a few seconds.4. Examine the output in the Map ViewWhen the run completes, the Job Completion dialog appears. Click the OK button.When the run completes the BLAST Window appears as the Map View (Figure 1).Make the BLAST Window active.Figure 1: BLAST Window with the Map ViewThe Map View gives a graphical representation of the hits found, displayed as one line per sequence. The bars are colored according to the bit score of the hits. A legend for the coloring is displayed at the top of the Map View. The higher the bit scores are better.The query sequence is displayed on top of the view as a ruler with residue index. The view can be zoomed in and out using the View | Transform commands, the scroll button on the mouse, or the control key and + or – keys in the keypad. When the view is scrolled out to its full size, the Ruler is changed to display individual residues.You may hover the mouse over any hit on the Map View and information about the hit is displayed.Place the mouse over the first hit and wait for the popup to appear.The popup text box presents the description of the sequence, the sequence accession number, the start and end position of the query sequence and the start and end of the hit sequence, and the scores of the hit.Note that the first hit is for histone deacetylase 8 represented by PDB file 1T64 (13).This is reassuring as we want to build a model of a histone deacetylase. In the original paper by Wang et al., the structure 1T64 was not available.Move the mouse to the second hit. Note that this hit is a histone deacetylase-like protein (HDLP) represented by PDB file 1C3P (5).The HDLP found here is virtually identical to the protein used in the original modeling study by Wang and co-workers, 1C3R (5). So, we may say that we have found the same template as used in their study. We do not get the exact same hit 1C3R due to the use of the nonredundant database.Move the mouse to the third hit. Note that this hit is also a histone deacetylase-like protein but a bacterial homologue histone deacetylase-like amidohydrolase. It is represented by PDB file 1ZZ1 (10).This hit, as was 1T64, was not available at the time of the original Wang et al. study.Hits may be selected by left clicking on the bars with the mouse. To add a specific hit to the current selection, hold down the shift or control key while clicking with the mouse.Figure 2: BLAST search results displayed in the Table View5. Examine the hits in the Table ViewAnother view of the data is available as the Table View (Figure 2). The Table View shows the hits one line per sequence with additional information.Ensure nothing is selected in the Map View.At the bottom of the Map View are tabs. Click the Table View tab. The Table View now is displayed.The data reported is essentially the same as what was found in the Map View except in tabular form.The hits in the table can be sorted by each column by left-clicking on the column header. When the table is sorted, the order of the hits in the Map View is changed according to the order in the Table View.Hits in the Table View can be selected by left-mouse clicking on the row. These hits are also selected in the Map View. The reverse is also true; selecting a hit in the Map View also selects the hit in the Table View.Examine the top two hits in the Table View. In the E-value columns, the expectation value for the hit may be found. For both 1T64 and 1C3P, the very low expectation values indicate these are good hits. The hit 1ZZ1 also has a low expectation value but it not as low as the first two. Notice also the wide difference between the E-values for the first three hits and the remainder in the table.The E-value is the expectation of getting a hit with the same bit score by chance. A low value indicates a real hit. However, the E-value alone may not be sufficient. You also should consider the alignment length.In the Table View, examine the columns Sequence Length and Alignment Length. Note that the first two hits (1T64 and 1C3P) are aligned with HDAC1 over a significant portion of their lengths. The third hit 1ZZ1 is aligned over a shorter length. Finally, the remaining entries in the table cover much smaller portions of HDAC1.The last tab is for the Text View. It is the raw BLAST output as an ASCII text file.6. Load hit alignmentHits may be loaded into Discovery Studio in several ways.Return to the Map View.While holding down the shift key, left click on the top three hits.With the hits selected right-click in the Map View area.Select the command Load Sequence and Alignment.Also note the five load commands available.After a few moments, a new Sequence Window opens with the three hits and the original HDAC1 sequence (with the original name).From either the Map View or Table View, five loading options are available to load the sequences, alignments, and structures into the Sequence Window and 3D Window. These options are briefly described.Load Selected Sequences Loads the sequences of the selected hits into one SequenceWindowLoad Selected Structures Loads the protein structures of the selected hits into one 3DWindow. The sequences are extracted into one SequenceWindow if the Sequence Window preference optionAutomatically create sequence window is checked; it is offby default.Load Sequence and Alignment Loads the sequences of the selected hits and aligns them tothe query sequence according to BLAST or PSI-BLASTalignment. Sequence regions outside of the hit alignmentreported by BLAST or PSI-BLAST are de-aligned by theaddition of gaps to the sequence.Load Structure and Alignment Loads the protein structures of the selected hits, extracts theirsequences into one Sequence Window, and aligns thesequences to the query sequence according to BLAST orPSI-BLAST alignment.Load Aligned Regions Loads the alignments of the selected hits from BLAST orPSI-BLAST output.Load Sequence and Alignment and Load Structure and Alignment commands load the query sequence in its entirety into the Sequence Window. Gaps are added to align the query sequence to the selected hits when the hits are loaded.Any commands that load structures are only valid when the database searched is PDB_nr95 or PDB, as we have here. For other databases, executing the two commands will bring up an error message stating that the PDB identification code is missing. The location of the PDB files is specified by Edit | Preferences... | Files Explorer | PDB Location.7. Save the sequence alignmentWe will save this alignment for future use.From the File menu, select the Save As… command.Set the Files of type: parameter to Sequence Files.Set the File Name to BLAST_search.Click the Save button.In normal work, you would probably want to save the three PDB files as well as they could be the templates we wish to use.8. Examine the sequence alignmentTake a moment to examine the sequence alignment.Activate the Sequence Window named Sequence Structure Alignment – Sequence Window.If you scroll down the sequence window, you will notice that a substantial number of residues are not matched. You will need to scroll past 1500 on the sequence ruler before you see any substantial alignment. The alignment will be found by looking for background color of the sequences.The Sequence Window displays the alignment of the hits with the unknown. The coloring is based on the sequence similarity among the hits and the target.9. Preparing for the next exerciseBefore proceeding with the next exercise we will close all the windows.From the Window menu, select the Close All command.If asked to save any data, select No.The BLAST algorithm is a useful algorithm to find templates for our unknown. It is a sensitive method to find close homologues from a database of sequences. If the sequence database was taken from a structural database such as the PDB, we may have template structures to use to build the homology modeling. For identifying more remote homologues, PSI-BLAST may be used and is described in the next exercise.References:1. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. 1990. Basic local alignmentsearch tool. J Mol Biol 215: 4032. Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, et al. 1997. Gapped BLASTand PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25: 33893. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, et al. 2000. The Protein DataBank. Nucleic Acids Res 28: 2354. Dayhoff MO, Schwartz RM, Orcutt BC. 1978. A model of evolutionary change inproteins. In Atlas of Protein Sequence and Structure, ed. MO Dayhoff, pp. 345.Washington, DC: National Biomedical Research Foundation5. Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, et al. 1999. Structures of ahistone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401: 188 6. Henikoff S, Henikoff JG. 1992. Amino acid substitution matrices from protein blocks.Proc Natl Acad Sci USA 89: 109157. Khochbin S, Verdel A, Lemercier C, Seigneurin-Berny D. 2001. Functional significanceof histone deacetylase diversity. Curr Opin Genet Dev 11: 1628. Korf I, Yandell M, Bedell J. 2003. BLAST. Sebastopol: O'Reilly & Associates, Inc. 339pp.。

Discovery-Studio-讲义中文

Discovery-Studio-讲义中文附录：准备一个PDB文件作为同源性建模模板同源建模的基本原理是，你映射的一个未知的蛋白质序列一种已知蛋白质的结构。

因此，如果你没有已知的蛋白质，或模板，你将无法建立模型。

模板的共同来源是蛋白质在结构生物信息学研究的实验室数据银行（目标）。

该网站RCSB是HTTP：/ /www.rcsb。

org /。

蛋白质数据库（PDB）可能是世界上领先的公共源三维生物分子数据（1）。

截至七月2006，超过37000项可在PDB。

每个月都有更多的人加入。

X射线衍射仪和其它固态技术占大多数的结构。

然而，超过5500的核磁共振结构还可用。

这些沉积的结构包括蛋白质，肽，核酸，碳水化合物，这些分子的配合物。

在发现工作室环境中工作的这些分子是一个关键的过程给你的建模工作。

这个练习如何准备一个PDB文件作为一个模板同源建模项目。

你将在课程中学习如何：•加载PDB文件直接从蛋白质数据银行，•生产和检验蛋白质报告，•清除晶体单元电池，•分裂分子，•删除不需要的组件，和保存已完成的文件。

1、开始发现工作室推出发现工作室客户端，如果它没有运行。

如果发现工作室已经在运行，从窗口菜单，选择关闭所有命令如果提示保存任何分子或数据，请选择“不”。

2注意：文件|打开网址…命令只会获得文件通过网络连接一个数据库服务器。

如果连接不可能返回错误。

检查你的导师或系统管理员，如果一个连接是可从您的车间位置。

从文件下拉菜单，选择命令打开网址。

在对话框中，网址应该是指目标网站。

更换与1t64 URL的最后四个字。

点击打开按钮。

如果一个PDB不能连接，所需的文件中的数据文件是可用的目录1t64_original.pdb。

在3D窗口中显示的结构是两人HDAC8蛋白的晶体结构在复杂的抑制剂，684个晶体的水，和几个离子。

抑制剂是曲古抑菌素A，一个很从“视图”菜单中选择“层次”命令。

的结构。

3、检查蛋白质报告在深入了解蛋白质，我们应该花一点时间来看看有什么。

Discovery Studio官方教程(Help-Tutorials) 分子对接前的准备受体和配体

Discovery Studio基本操作介绍在使用软件进行课题研究前，我们首先应该了解并掌握该软件使用的一些基本操作。

为后续的体系处理做好准备工作。

这个教程包括：●小分子配体准备●蛋白文件的处理小分子配体准备在Discovery Studio（DS）中，可以直接构建分子结构，也可以将在其它画图软件中画好的结构直接拷贝到DS中，本教程演示如何在DS中构建小分子结构。

1. 调用Sketching功能从View菜单下，打开Toolbars，选择Sketching。

Toolbars中将显示各种Sketching的工具，这些工具可以用来构建化合物的初始结构。

2. 利用Sketching构建化合物的3D空间构象打开一个分子显示窗口（Molecule Window），菜单栏File|New|Molecule Window。

注：DS中有四种窗口模式，包括Molecule window（显示分子结构），Protein Sequence Window （显示蛋白序列），Nucleotide Sequence Window（显示核酸序列），Script Window（显示脚本语言），因此我们需要根据载入的文件类型选择窗口。

DS中构建化合物的3D空间构象非常容易，也非常灵活。

本教程以以下化合物为示例，以图示的方法演示如何构建化合物的结构。

NHCl OOSOHNNH选择，在窗口中画出结构1。

点击（可以通过菜单栏View|Toolbars|Sketching调出）将其选中，然后选择菜单栏Chemistry|Bond|Aromatic得到结构2。

选择，鼠标指于芳环单键处并单击，构建稠环结构3。

选择，构建连接单键，再选择，鼠标指于C原子处并单击构建环状结构，最后得到结构4。

选择和构建单键和环状结构，选择再次点击相应的键就可以构建双键结构，最终可得到结构5。

更换元素类型，选中某个碳原子，选择菜单栏Chemistry|Element更换相应元素即可，最后得结构6。

Discovery Studio官方教程--拉伸动力学计算结合自由能

拉伸动力学计算结合自由能介绍拉伸分子动力学模拟可以使原来在微妙至秒时间范围内发生的生物物理过程在纳秒尺度内进行模拟，从而动态再现目前实验所无法提供的一些过程，如蛋白去折叠、配体解离和构象变化等过程。

上述这些过程可以通过在拉伸动力学模拟中让事件按照指定方向主动发生，而不像在标准分子动力学模拟中需要被动等待事件的发生。

本教程中，我们使用T4溶菌酶蛋白作为研究目标，模拟配体2-丙基苯酚从活性口袋的解离的过程。

具体见参考文献(J. Mol. Biol.2009, 394, 747-763). 本教程假定你已经熟悉建立和运行标准分子动力学模拟的过程。

对于该体系的SMD模拟比较复杂，因为配体的位置位于结合口袋的深处，而且将配体从结合口袋里拉出来的同时伴随着蛋白的散开，退出配体和蛋白的复原等过程。

1．准备蛋白配体模拟体系从菜单File | Open URL，在ID框中填入3HTB之后点击Open。

选择Macromolecules | Protein Report工具栏，点击Protein Report工具栏下方的Protein Report，通过蛋白报告可以检查出该蛋白是否有缺失残疾或其它需要校正的地方。

然后点击Prepare Protein工具栏下方的Clean Protein按钮，对蛋白质进行简单清理，该过程主要是包括删除蛋白文件中多余的构象，为蛋白加上N端和C端等过程。

接下来我们将手动删除蛋白中的晶体水分子和盐。

通过Ctrl+H打开Hierarchy View窗口，见下图，选择Water点击键盘上的Delete删除水分子。

另外第二个A链是磷酸根基团、BME残基和JZ4配体。

删除磷酸根基团和BME残基，保留JZ4配体和蛋白。

到这里，体系已经准备好了，接下来是给体系加入立场参数和水盒子，然后准备动力学模拟。

在做拉伸动力学之前需要使用标准动力学方法将复合物进行能量最小化，短的平衡过程和动力学模拟过程。

选择Simulation | Change Forcefield工具栏，在其下方的Forcefield中选择CHARMm力场，Partial Charge中选择Momany-Rone电荷，之后点击Apply Forcefield应用所选的力场和电荷。

Discovery Studio 2.5操作教程

蛋白质结构预测技术简介简介蛋白质结构的解析对其功能的理解至关重要。

然而，由于技术手段的限制，利用实验方法（主要为X-ray，NMR）解析蛋白质结构投入大、周期长、风险大。

对于某些膜蛋白，只利用现有技术条件，其结构甚至无法解析。

另一方面，随着分子生物学技术的成熟及高通量测序技术的发展，越来越多的基因序列可以轻松被找到。

这造成了现代蛋白质科学中一个奇怪的现象：蛋白质序列数据的累积量及积累速度远远超过蛋白质结构。

这种序列与结构间不平衡的现象极大地限制了我们对蛋白质功能及其相关作用机理的理解。

所以我们需要一种能够简单、快速且相对准确的技术来确定蛋白质的空间结构。

蛋白质建模技术可以很好的解决上面的问题。

该方法利用信息技术的手段，可以直接从蛋白的一级结构（氨基酸序列）预测蛋白质的高级结构（主要为三级结构）。

根据最新一届国际建模大赛（CASP）的分类，目前主要的蛋白质建模方法包括两种：基于模板的建模（Template-based Modeling）和自由建模（Free Modeling）。

前者又包括两种方法：同源建模法（Homology Modeling）和“穿线法”（Threading）。

后者主要以从头计算法（ab initio）为主。

所有的建模方法中，以同源建模法(Homology Modeling)使用最为广泛，预测结果的准确性最大。

同源建模的理论基础为蛋白质三级结构的保守性远远超过一级序列的保守性。

因此，人们可以通过使用一个或多个已知结构的蛋白（模板蛋白，template）来构建未知结构蛋白（目标蛋白，target）的空间结构。

其主要的步骤包括：1.搜索用于建模的template(s)2.将target与templates进行比较3.将步骤(2)中的比较信息用于建模Discovery Studio为用户提供了一整套利用Homology Modeling方法自动预测蛋白质空间结构的工具。

用户只需要提供蛋白质的氨基酸序列就可以轻松完成模型构建及模型可信度评估的工作。

DS_CDOCKER原理

培训内容
• DS中的分子对接简介 • DS CDOCKER概述
• DS单C击DO此CK处ER编原理辑简母介版标题样式
• DS CDOCKER参数设置技巧 • DS CD单O击CK此E处R编应辑用母实版例副标题样式 • DS CDOCKER hands-on练习 • Q&A
Copyright ©2010, Neotrident Technology Ltd. All rights reserved.
辅酶NAD+结合
Copyright ©2010, Neotrident Technology Ltd. All rights reserved.
应用实例——脱氢酶与底物及辅酶的结合作用（六）
分子对接研究底物、辅酶、Zn离子与受体的结合——结合模式（2D图）底物（L-阿拉伯糖醇）、Zn离子结合
单击此处编辑母版标题样式
应用实例——脱氢酶与底物及辅酶的结合作用（二）
单击此处编辑母版标题样式
单击此处编辑母版副标题样式
Copyright ©2010, Neotrident Technology Ltd. All righ脱氢酶与底物及辅酶的结合作用（三）
构建脱氢酶同源模型
单击此处编辑母版标题样式
• DS单C击DO此CK处ER编原理辑简母介版标题样式
• DS CDOCKER参数设置技巧 • DS CD单O击CK此E处R编应辑用母实版例副标题样式 • DS CDOCKER hands-on练习 • Q&A
Copyright ©2010, Neotrident Technology Ltd. All rights reserved.
Copyright ©2010, Neotrident Technology Ltd. All rights reserved.

DiscoveryStudio2.1中文教程

DiscoveryStudio2.1中⽂教程DS2.1教程介绍●⽤户界⾯和⿏标UI and mouse●打开并游览数据opening and viewing a data组合库设计●枚举组合库enumerate library●Pareto optimization of a combinatorial subset library药效团Pharmacophore●创建药效团（基于结构）creating pharmacophores (structure-based)●配体分析器ligand profiler●通⽤特征药效团⽣成common feature pharmacophore generation●创建和使⽤基于⽚段的药效团creating and using fragment-based pharmacophores●创建特定特征creating custom features蛋⽩质同源模建protein modeling●同源模建细胞外淀粉酶●Loop 构建Looper with antibodies●ZDOCK定量构效关系QSAR●建⽴⼀个QSAR⽅程building a QSAR equation受体配体相互作⽤Receptor-ligand interaction●使⽤libdock完成⼩分⼦对接Docking small molecules with libdock模拟Simulation●带有限制体⼩肽的模拟simulation of a small peptide with restraints (protein simulation)●在最⼩化之前之后，使⽤能量计算协议（QM-MM）计算能量去测定活⼒，rank order pose和⽐较energies using the calculate energy （QM-MM）protocol to determine energies，rank order poses and compare energies before and after minimization静电势计算Electrostatics●泊松玻尔兹曼——有限差分●计算蛋⽩质离⼦化和残基的pK●计算电势●计算溶剂化能开发客户端Developer Client⽤户界⾯和⿏标教程需要数据⽂件：1TPO.pdb 和1BVN.pdb背景可视化和基本的结构分析⼯具在⽣物和⽣化系统中是很重要的。

Discovery Studio官方教程--预测蛋白质聚集、水溶性、粘度、可开发性等性质

预测蛋白聚集位点（Protein Aggregation）教程介绍抗体等具有治疗功能的蛋白，如果处于比较高的浓度下，会有发生聚集的趋势。

这会导致抗体的活性下降，并引起免疫反应。

抗体的聚集趋势计算是一种衡量蛋白表面氨基酸聚集倾向性的指标。

具有比较高的聚集趋势得分的位点表明了该区域的氨基酸倾向于发生聚集。

因此这些位点的预测，使得我们可以通过氨基酸定点突变的方法来改造蛋白，增强其稳定性。

本教程使用Calculate Aggregation Scores对一个全长IgG1抗体分子(PDB号为1h2h)进行蛋白聚集位点的预测计算，并分析预测的结果。

本教程涵盖如下内容：●聚集趋势得分的计算●分析蛋白聚集位点聚集趋势得分计算在文件浏览器（Files Explorer）中，展开Samples | Tutorials | Protein Modeling文件夹，双击1hzh.pdb文件。

DS将在一个新的3D窗口中打开该蛋白。

图1 1hzh分子窗口Ctrl+H打开Hierarchy窗口，然后选中Water，点击Delete删除蛋白结构中的结晶水分子。

在工具浏览器（Tools Explorer）中，展开Simulation | Change Forcefield，将Forcefield设为CHARMm Polar H，然后点击Apply Forcefield，这将为蛋白赋上CHARMm Polar H力场。

图2 Apply Forcefield设置界面在工具浏览器（Tools Explorer）中，展开Macromolecules | Predict Protein Aggregation工具面板，点击Calculate Aggregation Scores。

在弹出的参数设置界面中，将Input Typed Protein设为1hzh:1HZH，将Cutoff Radius设为5,7,10。

点击Run运行该任务。

该任务在奔腾4，2Gb内存和2.8GHz的计算机平台上运行大约需要3分钟。

Discovery Studio官方教程--药物设计之片段生长

Discovery Studio Grow Scoffold教程Grow Scoffold –活性位点先导化合物优化介绍先导化合物优化是一个复杂过程，为了得到一个临床前候选药物，通常需要对有前景化合物及骨架不断地进行化学结构优化，以提高化合物的活性、选择性、生物利用度、药效及药代动力学性质，并降低毒性。

该过程通常是药物开发过程中的瓶颈。

通过使用实用且有效的先导化合物优化软件，根据可获取的化合物试剂的快速推荐出容易合成的候选化合物的结构。

基于结构的先导化合物优化主要集中于蛋白靶点的活性位点的化合物结构的设计。

Grow Scaffold工具可以根据蛋白靶点活性位点的特点，通过基于化学反应的原位生长（reaction-based in situ enumeration）方法来找出那些能够产生潜在化合物的试剂，并对它们进行打分排序。

p38α是一个典型的丝氨酸/苏氨酸蛋白激酶，属于丝分裂原活化蛋白激酶（mitogen activated protein kinase）家族。

它在内皮、免疫和炎性细胞中广泛表达，在肿瘤坏死因子和白细胞介素- 1等促炎症细胞因子产生的调控中扮演着重要作用。

实验已经证明，选择性地抑制其中任何一个细胞因子都能够有效治疗各种炎症和免疫疾病，如风湿性关节炎、炎症性肠病,败血性休克,和骨质疏松症。

二芳基脲是p38α的一个先导化合物，BoehringerIngelheim首先对它开展了先导化合物优化，随后Pfizer也开展了相关研究（图1）。

图1 p38α的先导化合物及优化过的先导化合物在本教程中你将使用Grow Scaffold流程来重现BoehringerIngelheim及Pfizer通过结构优化所发现的化合物。

本教程分为两部分：（一）使用基于反应的原位生长方法产生优化过的先导化合物（二）使用自定义反应来产生先导化合物（一）使用基于反应的原位生长方法产生优化过的先导化合物1.执行优化计算图2蛋白质三维结构示意图复合物结构采用PDB号为1KV2的晶体结构，本教程中所采用的该结构文件已经从PDB 库中下载并经过Prepare Protein模块处理。

Discovery Studio官方教程(Help-Tutorials) 可视化分子对接非键作用

Discovery Studio Analyze Ligand Poses教程介绍分子之间的非键相互作用是生命体系中分子识别的基础。

在基于结构的药物设计过程中，识别和优化配体分子和受体分子间的相互作用是一个基本过程，因此，全面细致的分析非键相互作用非常关键。

本教程将采用热稳定的腺苷A2A受体和反相激动剂ZM241385的复合物，其中A2A受体是G-蛋白偶联受体，是帕金森氏症的药物靶标，其拮抗剂Preladenant正处于临床阶段。

本教程将分析对接至A2A受体的配体分子构象。

执行计算并分析结果在文件浏览器（Files Explorer）中，双击打开Samples|Tutorials|Receptor-Ligand Interactions|3pwh_dockedposes.dsv。

打开一个分子对接结果，包含3pwh蛋白分子和多个小分子的对接构象。

（图1）说明：对接分子共有50个，具有一定多样性，其中20个为参照分子，带有CHEMBL前缀，30个为诱饵分子，带有ZINC前缀。

这50个分子基于Dock Ligands （CDOCKER）模块对接至已经预处理过的腺苷A2A受体分子，最终得到3pwh_dockedposes.dsv文件中的对接结果。

本教程通过对该对接结果的分析来获取重要的非键相互作用信息，从而进一步优化虚筛流程。

图1 3pwh对接结果在工具浏览器（Tools Explorers）中，展开Receptor-Ligand Interactions |View Interactions，点击Analyze Ligand Poses。

相应的参数出现在参数浏览器中。

点击Input Ligands参数项，下拉列表中选择3pwh_dockedposes:All，选中3pwh_dockedposes 窗口中所有配体构象。

其余参数保留默认设置，点击Run运行任务。

（图2）点击Background让任务后台运行，等待任务完成。

Discovery Studio官方教程(Help-Tutorials) 分子动力学模拟

Discovery Studio Molecular Dynamics教程Molecular Dynamics –分子动力学方法介绍分子动力学(Molecular Dynamics, MD)是分子模拟中最常用的方法之一。

该方法基于分子力场，能够动态的描述分子的运动状况，继而描述生命的动态过程。

分子动力学在生命科学领域中的应用非常广泛，如蛋白质折叠的机理研究、酶催化反应的机理研究、与功能相关蛋白质的运动研究、生物大分子大范围构象变化的研究等等。

近几十年来，分子动力学方法已经成功的运用于大分子体系低能量构象的模建、X射线晶体衍射以及NMR实验结果的处理。

[1,2]现在分子动力学方法已经成了理论生物学研究中必不可少的方法之一。

[3,4]分子动力学模拟主要包括如下几个步骤：1.模拟体系升温过程（Heating Stage）2.模拟体系平衡过程（Equilibrium Stage）3.模拟体系采样过程（Production Stage）4.分析体系的目标性质（Analysis）然而，由于一般的待模拟体系的初始结构或多或少的存在缺陷（比如，初始结构不完整或存在不合理的结构区域），所以我们往往需要对初始结构进行预处理才能进行分子动力学模拟。

一个完整的分子动力学模拟过程应包括如下几个步骤：1.初始结构检查及预处理2.给模拟体系赋力场参数3.考虑溶剂效应4.初始结构能量最小化5.动力学模拟（包括升温、平衡、采样）6.结果分析目前，常用的分子动力学模拟软件都基于Unix（Linux）操作系统。

实施每一个模拟的步骤都需要特定的命令来调用相关的程序对模拟体系进行处理。

同时，模拟者还需要熟知每个参数的意义并定义相关的参数值。

最终分析过程也需要配合其他软件才能完成。

这对初级分子动力学模拟者而言是非常困难的（模拟者不仅需要掌握分子动力学软件的使用命令，还需要掌握操作系统相关的命令）。

为了解决这样的问题，Discovery Studio为用户提供了基于窗口的分子动力学模拟工具。

Discovery studio简介

Discovery Studio介绍Discovery Studio™(简称DS), 基于Windows/Linux系统和个人电脑、面向生命科学领域的新一代分子建模和模拟环境。

它服务于生命科学领域的实验生物学家、药物化学家、结构生物学家、计算生物学家和计算化学家，应用于蛋白质结构功能研究，以及药物发现。

为科学家提供易用的蛋白质模拟、优化和药物设计工具。

通过高质量的图形、多年验证的技术以及集成的环境，DS将实验数据的保存、管理与专业水准的建模、模拟工具集成在一起，为研究队伍的合作与信息共享提供平台。

建立在最新的流程管理平台Pipeline Pilot基础上的DS让数据的共享和交流变得更为方便和简洁。

DS中的部分功能流程(protocols)可以在Pipeline Pilot中进行编辑和组合，编辑组合而得的新流程可以导入Discovery Studio中使用，这样使得科研流程的方便共享成为可能。

同时，Pipeline Pilot这个开放平台技术还为使用者整合自己的或第三方的软件工具提供了接口。

科研人员可以在一个统一的平台上完成从基因到先导化合物设计的一系列工作，并且可以通过web形式共享研究成果。

DS的服务器-客户端模式使得科研人员能够最方便且最大限度地实现计算资源共享。

DS目前的主要功能包括：蛋白质的表征（包括蛋白-蛋白相互作用）、同源建模、分子力学计算和分子动力学模拟、基于结构药物设计工具（包括配体-蛋白质相互作用、全新药物设计和分子对接）、基于小分子的药物设计工具（包括定量构效关系、药效团、数据库筛选、ADMET）和组合库的设计与分析等。

DS可以应用于生命科学以下研究领域：新药发现，生物信息学，结构生物学，酶学，免疫学，病毒学，遗传与发育生物学，肿瘤研究。

Discovery Studio功能模块简介- 基本界面和显示模块Discovery Studio StandaloneDiscovery Studio Visualizer Client- 蛋白质模拟模块DS MODELERDS Protein RefineDS Protein HealthDS Protein FamiliesDS Sequence Analysis- 基于结构的药物发现和设计模块DS Flexible DockingDS LigandFitDS LigandScoreDS LibDockDS CDOCKERDS Protein DockingDS LudiDS De Novo EvolutionDS LigandFit CAP/ DS Ludi CAPDS GOLD interface- 基于药效团的药物发现和设计模块DS Catalyst ConformationDS Catalyst HypothesisDS Catalyst SBPDS Catalyst ScoreDS Catalyst ShapeDS Catalyst DB BuildDS Catalyst DB SearchDS De Novo Ligand BuilderHypoDBPCDB (PharmaCoreDB)- 基于小分子的药物发现和设计模块DS QSARGFA ComponentV AMP Descriptors Component/ DMol3 Descriptors ComponentDS Library DesignDS ADMETDS TOPKAT- 分子力学和分子动力学计算模块DS CHARMmDS CHARMm LiteDS CFF (高级II类力场)DS MMFF (Merck Molecular Force Field)- 分析模块DS BiopolymerDS Analysis基本界面和显示模块·Discovery Studio Standalone可视化界面，是利用Discovery Studio软件进行分子设计和模拟的基础，支持服务器-客户端安装在同一台机器上的运行模式。

Discovery Studio官方教程(Help-Tutorials) 创建3D QASR模型

采用能量格点作为描述符构建PLS模型（3D-QSAR）教程介绍药物设计即试图发现能够同生物大分子靶标在形状（steric）和电荷（静电势）上互补的小分子。

与2D-QSAR相比，3D-QSAR方法更能间接反映配体小分子和蛋白大分子之间的非键相互作用特征，具有更加丰富的物理化学内涵，因此得到了迅速的发展和广泛的应用。

3D-QSAR模型时基于小分子的立体（steric）和静电（electrostatic）场构建的回归模型，可以用于预测未知配体小分子的活性及观察受体-配体间有利和不利的相互作用。

本教程利用能量格点作为描述符构建了一个偏最小二乘（PLS）模型。

该能量格点是通过两种用于测量静电势和立体效应的探针计算得到的。

本教程包括以下步骤：♦构建3D-QSAR模型♦观察分析结果♦基于3D-QSAR模型预测活性3D QSAR模型的构建在构建3D QSAR模型之前，需要对训练集分子进行叠合，叠合好坏决定了最终模型的可信度。

叠合方式一般有以下几种：♦如果配体分子都来源于晶体结构且都与同一靶标相结合，则可以直接使用晶体结合构象♦如果有配体小分子的药效团模型，则可将配体小分子匹配至药效团模型以实现对配体小分子的叠合♦可直接基于配体小分子的公共骨架进行叠合♦可将配体小分子公共骨架中的药效团特征元素加以提取，用于构建药效团模型，再通过配体药效团的匹配流程（Ligand Pharmacophore Mapping）进行小分子的叠合♦可基于立体场和静电场通过场匹配的方式进行小分子的叠合（Structure | Superimpose | Molecular Overlay…）1. 3D-QSAR的构建在文件浏览器（Files Explorer）中，展开Samples | Tutorials | QSAR，双击trainingset.sd。

在分子窗口中打开一个表格，共14行，即14个训练集分子，该分子事先已进行叠合。

在文件浏览器（Files Explorer）中，展开Samples | Tutorials | QSAR，双击testset.sd。

分子对接相互作用力 discovery studio

分子对接相互作用力discovery studio分子对接是一种主要用于计算机辅助药物设计的方法，可用于模拟和预测药物与靶标分子之间的相互作用。

在分子对接中，一方是药物分子（ligand），另一方是靶标分子（receptor）。

这两个分子通过非共价相互作用力进行结合，形成稳定复合物。

因此，对于药物发现研究而言，了解药物和靶标分子之间相互作用力的特性至关重要。

Discovery Studio是一种用于计算机辅助药物设计和药物发现的软件平台。

它内置了多种用于分子对接的工具和算法，可以帮助研究人员进行药物分子的筛选和优化，提高研发效率。

本文将以Discovery Studio的分子对接工具为主题，介绍其在药物发现中的应用和相互作用力的计算方法。

一、Discovery Studio分子对接的原理及流程在Discovery Studio中，分子对接的过程可以大致分为以下几个步骤：准备受体结构、准备配体结构、建立格点和计算能量。

1. 准备受体结构受体结构一般是指药物的靶标蛋白，可以从真实蛋白结构数据库中获取。

在进行分子对接之前，需要对受体结构进行优化和准备工作。

这包括去除水分子、修复缺失的原子、填充缺失的氢原子，并对蛋白进行能量最小化的处理。

2. 准备配体结构配体结构是指药物分子或其他小分子化合物。

首先，需要将配体结构进行优化和准备工作。

这包括去除水分子、修复缺失的原子、填充缺失的氢原子，并对配体进行能量最小化的处理。

此外，需要确定配体的荷电状态和形式，如药物分子的离子化状态。

3. 建立格点在分子对接过程中，通常会建立一个三维网格（grid）作为搜索空间，用于计算配体与受体之间的相互作用力。

这个网格的构建需要选择合适的参数和方法。

一般而言，可以使用栅格框（grid box）来定义搜索空间的大小和位置。

4. 计算能量在分子对接过程中，需要计算配体与受体之间的相互作用能量。

这些能量包括范德华力、库仑力、极化等效力等。

Discovery Studio官方教程--构建具有活性预测能力的3D QSAR药效团

构建具有活性预测能力的药效团（Hypogen）教程介绍3D Quantitative Structure-Activity Relationship (QSAR) Pharmacophore Generation protocol可以基于一系列针对特定生物靶标具有明确活性数值的化合物构建出具有活性预测能力的药效团模型。

该算法首先构建得到活性分子能共享而非活性分子则不能共享的初始药效团模型，然后再经过模拟退火进行模型的进一步优化。

最终构建得到的模型可以预测化合物的活性，以及指导化合物的优化以提高其活性。

此教程中我们采用一系列已知活性值的训练集分子来构建一个3D QSAR药效团模型。

本教程包括以下步骤：●3D QSAR药效团的构建(训练集)●药效团结果分析◆叠合&成本分析（cost analysis）◆测试集●化合物的设计改造3D QSAR药效团的构建1. 训练集分子的准备本教程采用一系列选择性的雌激素受体调节剂（SERMs）[Broqi et al., 2009]来构建一个3D QSAR药效团模型用于预测新型小分子的活性。

在文件浏览器（Files Explorer）中，展开Samples | Tutorials | Pharmacophore，双击打开serm_ligands.sd。

在表格浏览器中可以看到一共有24行，代表了24个分子。

这些分子的名字（Name）、活性（Activ，可以为IC50或Ki值，且活性跨度需跨越4个数量级）和活性不确定度（Uncert）都已事先输入。

Activ值为SERMs对MCF7人体胸腺恶性肿瘤细胞增生的抑制活性IC50（μM）值，Uncert值为1.5（该值的设定取自于文献[Broqi et al., 2009]）。

在表格浏览器中，点击键和键，在3D Window中观察各个分子的结构特征。

2. 药效团特征元素的选取在表格浏览器中，右击鼠标并选择Color By Activity。

discoverystudio4.5教程

discoverystudio4.5教程
Discovery Studio 4.5是一款生物信息学和计算生物学软件套件，由Accelrys（现在是BIOVIA）开发。

它提供了一系列功能强
大的工具和功能，可用于蛋白质建模、分析、虚拟筛选、药物设计等任务。

要学习Discovery Studio 4.5的使用，可以参考以下教程：
1. 官方教程：Accelrys官方网站上提供了一些针对Discovery Studio 4.5的教程和在线帮助文档，可以登录官方网站查找相
关资源。

2. 在线教程：在互联网上可以找到一些免费的在线教程，如YouTube上的视频教程、论坛上的帖子等，这些教程可以帮助你了解Discovery Studio 4.5的基本操作和功能。

3. 书籍和教材：有一些专门针对Discovery Studio的书籍和教材，可以购买或借阅这些资料来深入学习和理解软件的使用。

4. 培训课程：有些机构或专业培训机构提供Discovery Studio
的培训课程，可以参加这些课程来系统地学习软件的使用技巧和应用。

5. 学术论文和研究文章：可以阅读与Discovery Studio相关的
学术论文和研究文章，了解其他研究者是如何使用该软件进行科学研究的。

请注意，Discovery Studio 4.5是商业软件，购买和使用需要相关许可证。

Discovery Studio官方教程--药物毒理学性质预测及结果分析

使用Discovery Studio进行化合物毒理性质预测（TOPKAT）教程介绍毒理学性质预测流程TOPKAT基于分子的2D结构对化合物的毒性及环境效应进行快速且准确地计算预测并加以验证。

该流程采用了一系列强大且经交叉验证过的定量结构毒性关系（QSTR）模型来评估各种毒性预测结果。

基于该流程，我们可以完成以下工作：•快速评估有机化合物一系列毒理学性质•检查子结构以及结构改造的结构毒性关系以及相关的作用机制•分子排名以用于实验测试或者进一步的开发•设计新的化合物因此采用TOPKAT流程进行毒性预测在节省药物上市时间，减少动物实验，评估人体健康风险以及药物研发流程的战略性部署等方面都起了非常重要的作用。

本教程主要介绍了在Discovery Studio中如何进行小分子化合物毒理学性质的预测，以及预测结果的分析。

本教程包括：•运行TOPKAT流程•分析预测结果Discovery Studio中计算的毒理学性质包括：•潜在发育毒性（Developmental Toxicity Potential ，DTP)•致突变性（Mutagenicity (Ames test)）•啮齿动物致癌性（Rodent Carcinogenicity）——包括NTP及FDA数据集•大鼠长期口服最低毒副反应水平（Rat Chronic Oral Lowest Observed Adverse EffectLevel，LOAEL）•皮肤致敏性（Skin Sensitization (GPMT) ）•皮肤刺激性（Skin Irritancy）•大鼠口服LD50（Rat Oral LD50）•最大耐受剂量（Maximum Tolerated Dosage）•黑头呆鱼LC50（Fathead Minnow LC50）•大型蚤EC50（Daphnia magna EC50）•VlogP•眼刺激性（Ocular Irritation）•吸入LC50（Inhalational LC50）•好氧生物降解性能（Aerobic Biodegradability）运行TOPKAT毒性预测流程1. 导入小分子化合物文件在文件浏览器（File Explors）中，展开Samples | Receptor-Ligand Interaction，双击打开1fvv_ligand.dsv文件，可以看到1个化合物显示在Molecule Window中。

Discovery Studio官方教程--采用QMMM的方法对配体结构在活性位点中进行优化

QM/MM结构优化目的：采用QM/MM的方法对配体结构在活性位点中进行优化。

所需功能和模块：Discovery Studio Client, DS CHARMm。

所需数据文件：1UZE.dsv所需时间：1小时介绍本教程中，对一个配体分子将对接到human testicular angiotensin I-converting enzyme中，采用QM/MM的方法来优化对接所得到的结合模式。

利用CDOCKER将配体分子对接到受体中，计算RMSD值，然后选择第一个Pose进行QMMM优化。

1．QM/MM优化对接得到的配体位置打开IUZE.dsv，在窗口中选中Zn离子以及与Zn离子配位的配体，两个HIS和一个GLU 氨基酸，点击鼠标右键，选中Group…选项，命名为QMgroup。

图1选中1UZE中非配体外的所有原子，然后点击Tools | Simulation | Setup Constraints | Create Fixed Atom Constraint，我们在接下来的QM/MM优化中只优化配体的空间结构，而保持金属蛋白的构型固定。

在这里，我们默认晶体中金属蛋白的位置是准确的，而CDOCKER得到的配体位置还需要refine，我们就沿用半柔性对接的思想，在QM/MM优化中，将金属蛋白的位置固定，而只优化配体的构型。

金属蛋白上每个原子的位置不进行优化，但是在计算能量的时候还是包含了整个体系。

（注意：QM的区域不仅包含配体，还包括Zn离子，两个HIS和一个GLU氨基酸。

）可以看到金属蛋白上蓝色的小球代表了位置上被束缚的原子，在1UZE下面能看到定义的名字“Fixed:fix_1”。

图2在Protocols浏览器中展开Simulation文件夹，双击Minimization (QM-MM)流程，流程对应参数在参数浏览器中打开。

在参数浏览器中，点击Input Typed Molecule参数，从下拉列表中选择“1UZE:1UZE”。

discoverystudio讲义中文

建模模板同源建模的基本原理是，你映射的一个未知的蛋白质序列一种已知蛋白质的结构。

因此，如果你没有已知的蛋白质，或模板，你将无法建立模型。

模板的共同来源是蛋白质在结构生物信息学研究的实验室数据银行（目标）。

该网站RCSB是HTTP：/ /。

org /。

蛋白质数据库（PDB）可能是世界上领先的公共源三维生物分子数据（1）。

截至七月2006，超过37000项可在PDB。

每个月都有更多的人加入。

X射线衍射仪和其它固态技术占大多数的结构。

然而，超过5500的核磁共振结构还可用。

这些沉积的结构包括蛋白质，肽，核酸，碳水化合物，这些分子的配合物。

在发现工作室环境中工作的这些分子是一个关键的过程给你的建模工作。

这个练习如何准备一个PDB文件作为一个模板同源建模项目。

1、开始发现工作室2制剂，684个晶体的水，和几个离子。

抑制剂是曲古抑菌素A，一个很好的研究组蛋白去乙酰化酶抑制剂（2）。

的结构。

3、检查蛋白质报告在深入了解蛋白质，我们应该花一点时间来看看有什么。

一种快连锁。

但我们要清楚我们几个非原子以及。

4、删除单元电池晶体单元单元在分子力学计算中的意义不大。

有时它只是更容易这个文件是由多个部分组成的。

我们可以通过层次结构查看组件其他练习窗口。

然而，我们实际上可以分开的组件的PDB文件更快的四的成分是蛋白质（1t64_a和1t64_b），配体（1t64_nonprotein），和结晶水（1t64_water）。

拆分命令的三个选项允许在如何处理对象的操作中有一定的灵活性。

所有打出的层次结构视图中所有链和非蛋白结构为独立的对象，并列出每个氨基酸序列为序列单独序列。

蛋白打出所有的蛋白链结构为独立的对象层次结构中的每个视图和列表的氨基酸序列为序列单独序列。

非蛋白打出配体，如为单独的对象的水域在层次视图其他非蛋白结构和列表的任何非蛋白多肽序列在序列视图分离的序列。