DNA und Zellen
Vorlesung 2004 Bioinformatik Einführung in die Molekularbiologie für Informatiker C. Frömmel
DNA Desoxyribonukleinsäure
Was noch ungelöst ist: Wie faltet sich z.b. MGTIIVHKGGFPFDRIIAGFKL VVCIIESSTGGLPGEWQQHNGG AQTYYCGDQNTVFAPTERIISA AGVLIKHRRSDFHTTKLMSACD
STRAP mit Proteasomen-Verwandten (E.coli, Hefe) (aus 143 Organismen Gille et al. J. Mol. Biol., 2003) 16% Identität und trotzdem gleich Faltung
Proteasom: 28 Untereinheiten Seitenansicht der Tonne Proteasom aufgeschnitten
Proteasom von oben Proteasom in der Mitte geschnitten
Proteasom (Sekundärstrukturen) Alle Untereinheiten haben einen ähnlichen Fold
Proteasom
Cyt C Cyt C mit gebundenen Wasser
Cytochrom C (mit Häm)
Nur ß-Faltblätter + Turns Antikörperfragment (mit gebundenem Antigen)
Antikörper Blick von oben Sehr unterschiedliche Peptide können sich manchmal an die gleiche Bindungsregion binden (Molekulare Mimikry, Kreuzreaktivität) GAEDLQKATPDLNQKL EWGGARIGLWRIT kllkgpl D-Peptid FAB fragments CB4-1 (anti-p24)
Chymotrypsin
Protein sein aktives Zentrum FK506 binding protein mit Ligand
Are you interested in process simulation? e.g. in prion growth? Pöschel, T., Brilliantov, N.V., Frömmel, C. Kinetics of Prion Growth. Biophys. Journal 85: 3460-3474 (2003)
1CSE subtilisin Carlsberg 1SBT subtilisin Are you interested molecular mimicry??
The needle-haystack problem Basics: optimization 7 dimensions Hoppe, A. and Frömmel, C. NeedleHaystack: A programm for the rapid recognition of local structures in large sets of atomic coordinates. J. Appl. Cryst. 36: 1090---1097.(2003)
ähnlich unähnlich Ser 221 His 64 Subtilisin
Comparison of all activ subunits on atomic level ß1 yeast compared to ß1 (cow) similar so or so dissimilar
Substrat eingepasst, undenkbar grobes Modell! COO- NH3+ substrate
Subtilisin mit Inhibitor
+ kleinen Ligand Thrombin + Hirudin
http://www.mpimf-heidelberg.mpg.de/~holmes/muscle/muscle2.html
http://www.mpimf-heidelberg.mpg.de/~holmes/muscle/muscle2.html
http://www.mpimf-heidelberg.mpg.de/~holmes/muscle/muscle2.html
http://www.mpimf-heidelberg.mpg.de/~holmes/muscle/muscle2.html
http://www.mpimf-heidelberg.mpg.de/~holmes/muscle/muscle2.html
http://www.mpimf-heidelberg.mpg.de/~holmes/muscle/muscle2.html
http://www.mpimf-heidelberg.mpg.de/~holmes/muscle/muscle2.html
http://www.mpimf-heidelberg.mpg.de/~holmes/muscle/muscle2.html
Hämoglobin: eine Kette von vieren Hämgruppe Nur Helices und Turns
4 Untereinheiten (2 alpha 2 beta) ergeben ein Hämoglobinmolekül (Quartärstruktur) Bei Sauerstoffbindung ändert sich (leicht) die Struktur
Hämoglobin
Hämoglobin
Bioinformatics was coming from...
Hanging on the structure determination of proteins (x-ray) Bioinformatics 1980
Later: Bioinformatics = Alignment?
The mouse in men Humanities in the mouse Proteasome subunit (ß,active) PRC7_MOUSE PRC7_HUMAN VHTGTTIMAVEFDGGVVVGSDSRVSAGTAVVN : VHTGTTIMAVEFDGGVVMGSDSRVSAGEAVVN RVFDKLSPLHQRIFCALSGSAADAQAIADMAAYQLELHGLELEEPPLVLA... : : : :... RVFDKLSPLHERIYCALSGSAADAQAVADMAAYQLELHGIELEEPPLVLA... 95% identical!
The mouse in men Humanities in the mous Time since common root Number of genes 75 Mio years Mouse men 28 000 35 000 28 000 35 000 Nucleotides 2,5 GB 2,9 GB Chromosomes 19 + X 21 + X homologoues genes Similarities of orthologoues proteins Sequenzhomology (total) 99 % Mediane 78,5 % (13 000 Paare) 40 %
? Arnold Schwarzenegger =
All protein pairs above the curve are showing similar fold and it follows Men=Mouse Schneider and Sander, 1991
Service: e.g. Mapping of SNPs on protein structures * Gille & Frömmel 2001 Network: Heart insufficiency Inborne heart diseases xyz-pro= myosin
protein structure/function prediction grey: Hypertrophic cardiomyopathy Myosin yellow: Dilatative cardiomyopathy Dähmlow et al. 2002
Today 1. Does it support protein structure/function prediction? 2. Does it help to find relevant information? 3. Does it help to structure large data sets?? 4. Does it accelerate drug design cycles???
Alle über der Kurve haben den gleichen Fold und damit die gleiche Struktur und damit die gleiche Funktion? Schneider and Sander, 1991
Alignment Primärstrukturen Proteasomenuntereinheiten und Verwandte siehe auch prot.doc SHEET HELIX COIL a1_1ryp.dssp.gz 001..gadRHITIFSPEgR.LyQVEyAfkATNQTN... a2_1ryp.dssp.gz 002 tdrysfslttfspsgk.lgqidyaltavkqg... a3_1ryp.dssp.gz 002 srrydsrttifspegr.lyqveyalesisha... a4_1ryp.dssp.gz 001..gydRALSIFSPDgH.IfQVEyAleAVKRG... a5_1ryp.dssp.gz 001...drgVSTFSPEgR.LfQVEySleAIKLG... a6_1ryp.dssp.gz 002 rnnydgdtvtfsptgr.lfqveyaleaikqg... a7_1ryp.dssp.gz 001 gtgydlsnsvfspdgr.nfqveyavkaveng... b1_1ryp.dssp.gz 001...lkkG...EV b2_1ryp.dssp.gz 001... b3_1ryp.dssp.gz 001...sdpSS... b4_1ryp.dssp.gz 001... b5_1ryp.dssp.gz 001... b6_1ryp.dssp.gz 001...qfnP...YG b7_1ryp.dssp.gz 001...tqqPI hs_ecoli.dssp 001... ap_mycobacteriumtuberculosis.embl 001...msfPYFISPEqAMrERSELarKGIARA... a1_1ryp.dssp.gz 030...INSLAVRG.kdCTVVISQKk...vPDKLLDPT.T...VS a2_1ryp.dssp.gz 032...VTSLGIKA.tnGVVIATEKk...sSSPLAMSE.T...LS a3_1ryp.dssp.gz 032...GTAIGIMA.sdGIVLAAERk...vTSTLLEQDT...STe a4_1ryp.dssp.gz 029...TCAVGVKG.knCVVLGCERr...sTLKLQDTRIT...Ps a5_1ryp.dssp.gz 027...STAIGIAT.keGVVLGVEKr...aTSPLLESD.S...IE a6_1ryp.dssp.gz 032...SVTVGLRS.ntHAVLVALKr...nADELSS...Y...QK a7_1ryp.dssp.gz 031...TTSIGIKC.ndGVVFAVEKl...iTSKLLVPQ.K...NV b1_1ryp.dssp.gz 007 SlgASIMAVTF.KDGVIlgADSRTTTGAYI.ANR...V...TD b2_1ryp.dssp.gz 001...ttiVGVKF.NNGvvIAADTRSTQGPIV.ADK...N...Ca b3_1ryp.dssp.gz 006 INGgiVVAMTG.KDCVAiaCDLRLGSQSLG.VSN...K...FE b4_1ryp.dssp.gz 001..mdiILGIRV.QDSviLASSKAVTRGISV.LKD...S...Dd b5_1ryp.dssp.gz 001...tttLAFRF.QGGiiVAVDSRATAGNWV.ASQ...T...Vk b6_1ryp.dssp.gz 007 DngGTILGIAG.EDFAVlaGDTRNITDYSI.NSR...Y...EP b7_1ryp.dssp.gz 006 VTGTSVISMKY.DNGviIAADNLGSYGSLL.RFN...G...Ve hs_ecoli.dssp 001...ttiVSVRR.NGHvvIAGDGQATLGNTV.MKG...N...Vk ap_mycobacteriumtuberculosis.embl 028...KSVVALAyaGGVLFVAEnP..SRSLQKI...SELyDR
Now we... 4-point pharmacophore z.b. ACE inhibitor Finn et al 1998
Bioinformatics is beginning: to provide both conceptual bases and practical methods for detecting systemic functional behaviours of the cell and the organism and methods to predict influence of anything on living systems.
What is missing??? Gene Genes?? mrna Gene(s) (mrnas)??(????????????????????????) protein(s) (fold function) proteins????????????????????????? cells Cells???????????????????????????? organs Organ??????????????????????????? organisms Genom?? (??????????????????????????????????) personalised health care
Steps forward: Experimental test systems Computational system biology Medical test systems Computational system medicine
bpi Credo 1 practise theory
Bioinformatics is going to the doctors Medical Faculty (Berlin, CUB)
The ultimate goal of all medical research is the reduction of morbidity and mortality through prevention and treatment!
e.g. Rheumatoide arthritis progression Ätiologie Pathogenese activity state therapy Berlinflame Supported by BMBF
DNA-Array Hybridisation synovectomy array-hybridisation RNA-extraction derivatisation AAAA AAAA TTTT cdna-synthesis UUUU
Goals of expressions analysis of genes Identification of important genes Pathogenesis and mechanisms of regulation Moleculare classifikation of arthritis identification of target genes Diagnostica, prognostica and therapeutica
Credo 2 phenotype genotype
Gene to physiology! Credo 2a physiology genotype
Neuroscience Berlin Neuroimaging centre (Villringer, Dirnagl)
Computational system biology Kinetic modelling of complex cellular networks under special Consideration of the metabolism of hepatozytes Co-ordinator: Dr. HG Holzhütter
We are important for real doctors but not so much in the case of enviromental causes of death or illness tobacco use unhealthy diet physical inactivity excessive alcohol use trauma and exposure to environmental toxins. infections? But...
We are important for real doctors (and researcher) forever in the case of renewable (evolving) diseases cancer (evolution to immortal cells) immune diseases (autoimmunity, allergic diseases..) infectious diseases (evolution of viruses and bacteria) mendelian diseases ((new) diseases in human evolution) and in therapies tailored for individuals and as fighters against data massifs!
Be carefull with -OMICS because the alignment shows:...genomics..proteomics \ METABOLOMICS...COMICS
Schluss!