山大生物信息学课件02从结构到结构生物信息学

1、From structure to structural bioinformatics and beyondThe Human Genome Project人类基因组计划是20世纪后半叶生命科学中最重大的事件Double every 18 monthsThere are now over 1000complete genomes!Where are we at?Attention now turns to theproteome: Protein identification and function Protein - protein interactions Whole pathways

2、Whole systems摩登(modern)的陷阱在科学技术高度发展，分子生物学,生物信息学等风靡世界的今天，现代的生命科学到底解决了哪些问题？生命到底是什么？这些最基本的问题，科学家还是茫然无以对答，仍然任凭宗教的说教！人类的科学研究正进入还原论的迷宫，而对于物质世界的整体性与规律性的研究已经看不到达尔文、牛顿及爱因斯坦的思想火花。导致的问题：学生无能力独立自主，开创未来。就算紧跟新知識，其实已经是落后至少5-10年。任何新知識都须要经过考驗。紧跟新知識，有可能是捕風捉影。片断琐碎，缺整体的认识。摩登(modern)的陷阱垃圾大戰 的 大學教育平時上課：教授丟垃圾，學生代表撿垃圾！考試前：

3、圾圾copy，各自回家作垃圾分類！進入考場：掃瞄垃圾場，傾倒垃圾！傾倒完畢，如釋重負！清倒夫 vs. 拾荒者 TIP 獨特的清倒夫能力！徹底的垃圾分類！捨得垃圾！你個人的情況？讀過多少本書(完整的)？屈服於摩登的誘惑？知識間是否有矛盾？空白？有無問題？清倒夫？ 拾荒者？企圖心？願景？ TIP 作禪打坐，靜思。捕捉剎那！现代的研究生必须要注意学习什么和怎样学的问题！研究不只在“puzzle solving”，更重要的是在探求ultimate (演化上和历史上)的问题。在这价值上，我们建立我们的生命哲学。这些问题的挑战，使我们的生活更富有，也使我們更能瞭解人类生存的意义。仅仅信息数据的增加、数据库

4、的增多，不足全面解释复杂生命现象，必须注意新方法，新思路，新算法的学习。Nature 415, 141 - 147 (2002) Human genome statisticsTAACCCTAACCCTAACCCTAACCCTAACCCTAACCCTAACCCTAACCCTAACCCTAACCCTAACCCTAACCCTAACCCTAACCCTAACCCTAACCCTAACCCTAACCCAACCCTAACCCTAACCCTAACCCTAACCCTAACCCTAACCCCTAACCCTAACCCTAACCCTAACCCTAACCTAACCCTAACCCTAACCCTAACCCTAACCCTAA

5、CCCTAACCCTAACCCTAACCCCTAACCCTAACCCTAAACCCTAAACCCTAACCCTAACCCTAACCCTAACCCTAACCCCAACCCCAACCCCAACCCCAACCCCAACCCCAACCCTAACCCCTAACCCTAACCCTAACCCTACCCTAACCCTAACCCTAACCCTAACCCTAACCCTAACCCCTAACCCCTAACCCTAACCCTAACCCTAACCCTAACCCTAACCCTAACCCCTAACCCTAACCCTAACCCTAACCCTCGCGGTACCCTCAGCCGGCCCGCCCGCCCGGGTCTGACCTGAGG

6、AGAACTGTGCTCCGCCTTCAGAGTACCACCGAAATCTGTGCAGAGGACAACGCAGCTCCGCCCTCGCGGTGCTCTCCGGGTCTGTGCTGAGGAGAACGCAACTCCGCCGGCGCAGGCGCAGAGAGGCGCGCCGCGCCGGCGCAGGCGCAGACACATGCTAGCGCGTCGGGGTGGAGGCGTGGCGCAGGCGCAGAGAGGCGCGCCGCGCCGGCGCAGGCGCAGAGACACATGCTACCGCGTCCAGGGGTGGAGGCGTGGCGCAGGCGCAGAGAGGCGCACCGCGCCGGCGCAGGCGCAGAG

7、ACACATGCTAGCGCGTCCAGGGGTGGAGGCGTGGCGCAGGCGCAGAGACGCAAGCCTACGGGCGGGGGTTGGGGGGGCGTGTGTTGCAGGAGCAAAGTCGCACGGCGCCGGGCTGGGGCGGGGGGAGGGTGGCGCCGTGCACGCGCAGAAACTCACGTCACGGTGGCGCGGCGCAGAGACGGGTAGAACCTCAGTAATCCGAAAAGCCGGGATCGACCGCCCCTTGCTTGCAGCCGGGCACTACAGGACCCGCTTGCTCACGGTGCTGTGCCAGGGCGCCCCCTGCTGGCGACTAGGGCA

8、ACTGCAGGGCTCTCTTGCTTAGAGTGGTGGCCAGCGCCCCCTGCTGGCGCCGGGGCACTGCAGGGCCCTCTTGCTTACTGTATAGTGGTGGCACGCCGCCTGCTGGCAGCTAGGGACATTGCAGGGTCCTCTTGCTCAAGGTGTAGTGGCAGCACGCCCACCTGCTGGCAGCTGGGGACACTGCCGGGCCCTCTTGCTCCAACAGTACTGGCGGATTATAGGGAAACACCCGGAGCATATGCTGTTTGGTCTCAGTAGACTCCTAAATATGGGATTCCTGGGTTTAAAAGTAAAAAATAA

9、ATATGTTTAATTTGTGAACTGATTACCATCAGAATTGTACTGTTCTGTATCCCACCAGCAATGTCTAGGAATGCCTGTTTCTCCACAAAGTGTTTACTTTTGGATTTTTGCCAGTCTAACAGGTGAAGCCCTGGAGATTCTTATTAGTGATTTGGGCTGGGGCCTGGCCATGTGTATTTTTTTAAATTTCCACTGATGATTTTGCTGCATGGCCGGTGTTGAGAATGACTGCGCAAATTTGCCGGATTTCCTTTGCTGTTCCTGCATGTAGTTTAAACGAGATTGCCAGCACCGGGTATC

10、ATTCACCATTTTTCTTTTCGTTAACTTGCCGTCAGCCTHuman genome has 3 billion basesIf you print 100 characters per line and 50 lines per page, youll fill 600,000 pages, stacked 60 meters high.If you read one base per second, nonstop, it will take you 100 years.Total: 100 gigabases in 165,000 organisms.It will ta

11、ke you 3,300 years to finish reading 教与学授人以鱼,不如授人以渔。 中国古训认识一位巨人的研究方法，对科学的进步并不比发现本身更少用处，科学研究的方法通常是极富兴趣的部分。 （法）拉普拉斯 Laplace数据、信息、知识数据 (Data) 从观察事件所作的记录。信息 (Information) 经过处理后具有意义的数据。知识 (Knowledge) 思考信息、配以行动的能力Data, Information, Knowledge From Data to Information.10, M, 0, 10, 10, 0, 0, 0, SUBACUTE, 37

12、, 2, 1, 0,15,-,-, 6000, 2, 0, abnormal, abnormal,-, 2852, 2148, 712, 97, 49, F,-,multiple,2137, negative, n, n, ABSCESS,VIRUS12, M, 0, 5, 5, 0, 0, 0, ACUTE, 38.5, 2, 1, 0,15, -,-, 10700,4,0,normal, abnormal, +, 1080, 680, 400, 71, 59, F,-,ABPC+CZX, 70, negative, n, n, n, BACTERIA, BACTERIANumerical

13、attribute categorical attribute missing values class labelsIF cell_poly 15 THEN Prediction = VIRUS 87,5%confidence, predictive accuracyRaw data is rarely of direct benefit. How to acquire knowledge for knowledge-based systems remains as the main difficult and crucial problem.Infomation Rich Knowledg

14、e Poor Benefits of Knowledge Discovery对结构进行研究是获取生命科学知识的重要途径生命科学成为有规律的知识得益于对其结构的研究方法生物体结构功能复杂、多样有序的、规律的利用、改造结构生物学The Strategy of Structural BiologyBreak down complexity so that the system can be understood at a fundamental levelBuild up a picture of the whole from the reconstruction of the high resol

15、ution piecesUnderstanding basic governing principles enables prediction, design, control Pharmaceuticals, biotechnologyImaging TechnologiesThought is impossible without an image.Aristotle,325 B.C.High Resolution Structural BiologyDetermine atomic structureAnalyze why molecules interact 要了解生命科学的奥秘及不同

16、物理、化学分子之间的特殊规律，必须对生物大分子的结构进行研究，只有这样，才能了解生命科学的规律。 1）结构是功能的基础，是物理化学性质的基础。 2）蛋白质结构有关明确的层次、功能研究的关系。生物大分子结构的研究获取生物大分子结构的三种策略之一：基于物理学方法直接测定蛋白质折叠不是通过随机搜索找到自由能最低的构象。如：100个氨基酸可采取3个不同位置，构象数为3100，即5*1047种可能，搜索一种可能的构象需要10-13s，要1.6*1027年，实际折叠时间为秒级，这一矛盾称为Levinthal疑题。之二：基于第一定律从头算,Protein folding获取生物大分子结构的三种策略之三：基于

17、生物信息学统计方法获取生物大分子结构的三种策略What is the ultimate goal of solving protein folding problem?MARLVSRTVRS GLRHYAKDVK FGADGRASML YGVDTLADAV AVTMGPKGRN VVIEQSWGSP KGANPVEVRRG VMKAVELLVA ELKKMSKDVT TPEEIAQVAT ISANGDSSVG KLISEAMKTV GNKGVITVKDG KTLHDELETI EGMKFDRGYI SPYFINTSKG AKVEFEKCLL LFSEKKISQV QDIVPALELAN KYR

18、KPIVIIA EDVDGEALTT LVLNRLKVGL QVAAVKAPGF GDNRKNTLKD MAIATGGTVFG DDANLLKIED VQISDLGEAE EVSITKDDTL ILRGKGKPED LEKRISMIED EMDQSTSEYEK EKLNERLAKL SKGVAVLKVG GASEVEVNEK KDRVTDALNA TRAAVEEGIV PGGGVALLRAL KAIENVKGEN TDQDKGIRIV QKAVREPIMT IVRNAGVDPS SVVEKVLASN ELPFGYDAMND TFVDMFKAGI IDPTKVIRTA LQDAAGVASL LA

19、TTECVVTE LPKEEPQMAA GMGGGMGGRYG RNVLIFERGV VFGKIGIIFL LDYGLSFRCL IISSDML Retro - protein folding problem MTVEYHKLDF GYPMMSDWWS AQEAAESDHN DAARVNTKMN AQWSCDERFV AASDFHKLCV AQWERTYIPL WGWHKPCLYUde novo Protein Design Why such interest in protein design? The first is the belief that the ultimate test o

20、f our understanding of protein structure is to design sequences that fold into the structures that we specify. The second is the hope that one day we will be able to design completely novel protein structures, possessing therapeutically or industrially important activities. High-resolution protein d

21、esign with backbone freedom. Harbury P.B., Plecs J.J., Tidor B., Alber T., Kim P.S. (1998) Science 282: 1462-1467. Design of b-sheet protein Design of a 20-amino acid, three-stranded b-sheet protein. Kortemme T., Ramirez-Alvarado M., Serrano L. (1998) Science 281: 253-256. Design of a bba protein De

22、 novo protein design: fully automated sequence selection. Dahiyat B.I., Mayo S.L. (1997) Science 278: 82-87. Design of a monomeric 23-residue polypeptide with defined tertiary structure. Struthers M.D., Cheng R.P., Imperiali B. (1996) Science 271: 342-345. Design of haem-binding protein Design, synt

23、hesis, and characterization of a photoactivable flavocytochrome molecular maquette. Sharp R.E., Moser C.C., Rabanal F., Dutton, P.L. (1998) Proc. Natl. Sci. U.S.A. 95: 10465-10470. Design and synthesis of multi-haem proteins. Robertson D.E., Farid R.S., Moser C.C., Urbauer J.L., Mulholland S.E., Pid

24、ikiti R., Lear J.D., Wand A.J., DeGrado W.F., Dutton P.L. (1994) Nature 368: 425-432. Design of novel metal-binding sites The construction of metal centers in proteins by rational design. Hellinga H.W. (1998) Fold. Des. 3: R1-R8. Metalloprotein design. Hellinga H.W. (1996) Curr. Opin. Biotechnol. 7:

25、 437-441. Protein design: novel metal-binding sites. Regan L. (1995) Trends Biochem Sci 20: 280-285. Novel metal-binding proteins by design. Klemba M., Gardner K.H., Marino S., Clarke N.D., Regan L. (1995) Nat. Struct. Biol. 2: 368-373. Design of the hydrophobic cores Design of proteins with hydroph

26、obic and polar amino acids. Micheletti C., Seno F., Maritan A., Banavar J.R. (1998) Proteins 32: 80-87. De novo design of the hydrophobic cores of proteins. Desjarlais J.R., Handel T.M. (1995) Protein Sci. 4: 2006-2018. Designing amino acid sequences to fold with good hydrophobic cores. Sun S., Brem

27、 R., Chan H.S., Dill K.A. (1995) Protein Eng. 8: 1205-1213. Folding models and design algorithms A free energy analysis by unfolding applied to 125-mers on a cubic lattice. Chung M.S., Neuwald A.F., Wibur W.J. (1997) Fold. Des. 3: 51-65. Computer search algorithms in protein modification and design.

28、 Desjarlais J.R., Clarke N.D. (1998) Curr. Opin. Struct. Biol. 8: 471-475. Optimizing potentials for the inverse protein folding problem. Chiu T.L., Goldstein R.A. (1998) Protein Eng. 11: 749-752. New algorithm for protein design. Deutsch J.M., Kurosky T. (1996) Phys. Rev. Lett. 76: 323-326. Automat

29、ed design of the surface positions of protein helices. Dahiyat B.I., Gordon D.B., Mayo S.L. (1997) Protein Sci. 6: 1333-1337. Coupling backbone flexibility and amino acid sequence selection in protein design. Su A., Mayo S.L. (1997) Protein Sci. 6: 1701-1707. Genetic algorithms for protein structure

30、 prediction. Pedersen J.T., Moult J. (1996) Curr. Opin. Struct. Biol. 6: 227-231. Rational protein design: Combining theory and experiment.Economy in protein design. Struthers M.D., Cheng B., Imperiali B. (1996) Science 271: 342-344. Protein design: a heirarchic approach. Bryson J.W. et al., DeGrado

31、 W.F. (1995) Science 270: 935-941. Guidelines for protein design: the energetics of beta sheet side chain interactions. Smith C.K., Regan L. (1995) Science 270: 980-982 The Context of StructureMoleculeStructural GenomicsPathwayStructural ProteomicsActivitySystems BiologyRPANERBERRRHierarchy of prote

32、in structuresProteins are polypeptide chainsThe building blocks (I)The building blocks (II)The building blocks (III)The building blocks (IV)Grouping amino acidsPeptide bond and backbone rotationRotational conformationRamachandran plotDisulfide bridgeMetal bindinga-helix (side chain)a-helix (dipole m

33、oment)a-helix (sequence patterns)a-helix (helical wheel)Helix-loop-helixCalcium-binding motifCalcium-binding motif (sequence signature)Beta-sheet (anti-parallel and paralle)Beta-sheet (arrangement & twist)Loops connecting b-strandsThe Greek key motifTopology diagrams for b-sheetsb-a-b motif (and han

34、dedness)The b-a-b-a motif丙糖磷酸异构酶Multi-domain proteins 胰凝乳蛋白酶尿激酶血浆酶原Alpha structuresRidge-in-groove interaction43Heptad repeat in coiled-coil a-helixHydrophobic side-chain interactionSalt-bridge helpsFour-helix bundle4-helix bundle: Knobs-in-holes interaction4-helix bundle: topologyLarge alpha structuresSickle-cell hemoglobinSickel-cell anemia & malariamutant oligomerizationHemoglobin &sick