SWISS-MODEL:

Giving the proteome a third dimension.

Torsten Schwede

Fortaleza, Brasil 1. August 2006

Torsten.Schwede@unibas.ch

Schweizerisches Institut für BioinformatikInstitut Suisse de BioinformatiqueIstituto Svizzero di BioinformaticaSwiss Institute of Bioinformatics

Introduction

gggtctctcttgttagaccagatctgagcctgggagctctctggctaactagggaacccactgcttaagcctcaataaagcttgccttgagtgcttcaagtagtgtgtgcccgtctgttgtgtgactctgatagctagagatcccttcagaccaaatttagtcagtgtgaaaaatctctagcagtggcgcctgaacagggacttgaaagcgaaagagaaaccagagaagctctctcgacgcaggactcggcttgctgaagcgcgcacggcaagaggcgaggggacggcgactggtgagtacgccaaaattttgactagcggaggctagaaggagagagatgggtgcgagagcgtcgatattaagcgggggaggattagatagatgggaaaaaattcggttaaggccagggggaaagaaaaaatatagattaaaacatttagtatgggcaagcagggagctagaacgattcgcagtcaatcctggcctattagaaacatcagaaggttgtagacaaatactgggacaactacaaccagcccttcagacaggatcagaagaacttagatcattatataatacagtagcaaccctctattgtgtgcatcaaaagatagatgtaaaagacaccaaggaagctttagataagatagaggaagagcaaaacaaaagtaagaaaaaagcacagcaagcagcagctgacacaggaaatagcagccaggtcagccaaaattaccccatagtgcagaacatccaggggcaaatggtacatcaggccatatcacctagaactttaaatgcatgggtaaaagtagtagaagagaaggctttcagcccagaagtaatacccatgttttcagcattatcagaaggagccaccccacaagatttaaacaccatgctaaacacagtggggggacatcaagcagccatgcaaatgttaaaagagaccatcaatgaggaagctgcagaatgggatagattgcatccagtgcatgcagggcctcatccaccaggccagatgagagaaccaaggggaagtgacatagcaggaactactagtacccttcaggaacaaatagcatggatgacaaataatccacctatcccagtaggagaaatctataagagatggataatcctgggattaaataaaatagtaaggatgtatagccctaccagcattctggacataaaacaaggaccaaaggaaccctttagagactatgtagaccggttctataagactctaagagccgagcaagcttcacaggaggtaaaaaattggatgacagaaaccttgttggtccaaaatgcgaacccagattgtaagactattttaaaagcattgggaccagcagctacactagaagaaatgatgacagcatgtcagggagtgggaggacccggccataaagcaagagttttggcagaagcaatgagccaagtaacaaattcagctaccataatgatgcagaaaggcaattttaggaaccaaagaaaaattgttaagtgtttcaattgtggcaaagaagggcacatagccaaaaattgcagggcccctaggaaaaggggctgttggaaatgtggaaaggagggacaccaaatgaaagattgtactgagagacaggctaattttttagggaaaatctggccttcccacaggggaaggccagggaattttcctcagaacagactagagccaacagccccaccagccccaccagaagagagcttcaggtttggggaagagacaacaactccctctcagaagcaggagctgatagacaaggaactgtatccttcagcttccctcaaatcactctttggcaacgaccccttgtcacaataaagataggggggcaactaaaggaagctctattagatacaggagcagatgatacagtattagaagaaataaatttgccaggaagatggaaaccaaaaatgatagggggaattggaggttttatcaaagtaagacagtatgatcaaatactcgtagaaatctgtggacataaagctataggtacagtattagtaggacctacacctgtcaacataattggaagaaatctgttgactcagattggttgcactttaaattttcccattagtcctattgaaactgtaccagtaaaattaaagccaggaatggatggcccaaaagttaaacaatggccattgacagaagaaaaaataaaagcattagtagaaatctgtacagaaatggaaaaggaaggaaaaatttcaaaaatcgggcctgaaaatccatataatactccagtatttgccataaagaaaaaagacagtactaaatggagaaaattagtagatttcagagaacttaataagaaaactcaagacttctgggaagttcaattaggaataccacatcccgcagggttaaaaaagaaaaaatcagtaacagtactggatgtgggtgatgcatatttttcagttcccttagataaagaattcaggaagtacactgcatttaccatacctagtataaacaatgagacaccagggattagatatcagtacaatgtgcttccacagggatggaaaggatcaccagcaatattccaaagcagcatgacaaaaatcttagagccttttagaaaacaaaatccagacatagttatctatcaatacatggacgatttgtatgtaggatctgacttagaaatagggcagcatagaacaaaaatagaggaactgagacaacatctgttgaagtggggatttaccacaccagacaaaaaacatcagaaagaacctccattcctttggatgggttatgaactccatcctgataaatggacagtacagcctatagtgctgccagaaaaggacagctggactgtcaatgacatacagaagttagtgggaaaattgaattgggcaagtcagatttacccagggattaaagtaaagcaattatgtagactccttaggggaaccaaggcactaacagaagtaataccactaacaaaagaagcagagctagaactggcagaaaacagggaaattctaaaagaaccagtacatggagtgtattatgacccatcaaaagacttaatagcggaaatacagaagcaggggcaaggtcaatggacatatcaaatttatcaagagccatttaaaaatctgaaaacaggaaaatatgcaagaatgaggggtgcccacactaatgatgtaaaacaattaacagaggcagtgcaaaaaataaccacagaaagcatagtaatatggggaaagactcctaaatttaaactacccatacaaaaagaaacatgggaaacatggtggacagagtattggcaagccacctggattcctgagtgggagtttgtcaatacccctcccttagtaaaattatggtaccagttagagaaagaacccataataggagcagaaactttctatgtagatggggcagctaacagggagactaaattaggaaaagcaggatatgttactaacaaagggagacaaaaagttgtctccataactgacacaacaaatcagaagactgagttacaagcaattcttctagcattacaggattctggattagaagtaaacatagtaacagactcacaatatgcattaggaatcattcaagcacaaccagataaaagtgaatcagagatagtcagtcaaataatagagcagttaataaaaaaagaaaaggtctacctgacatgggtaccagcgcacaaaggaattggaggaaatgaacaagtagataaattagtcagtactggaatcaggaaagtactctttttagatggaatagataaagcccaagaagaacatgaaaaatatcacagtaattggagggcaatggctagtgattttaacctgccacctgtggtagcaaaagagatagtagccagctgtgataaatgtcagctaaaaggagaagccatgcatggacaagtagactgtagtccaggaatatggcaactagattgtacacatttagaaggaaaaattatcctggtagcagttcatgtagccagtggatatatagaagcagaagttattccagcagaaacagggcaggaaacagcatactttctcttaaaattagcaggaagatggccagtaaaaacagtacatacagacaatggcagcaatttcaccagtactacagttaaggccgcctgttggtgggcaggaatcaagcaggaatttggcattccctacaatccccaaagtcaaggagtagtagaatctataaataaagaattaaagaaagttataggacagataagagatcaggctgaacatcttaagacagcagtacaaatggcagtattcatccacaattttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaactaaagaactacaaaaacaaattacaaaaattcaaaattttcgggtttattacagggacagcagagatccactttggaaaggaccagcaaagcttctctggaaaggtgaaggggcagtagtaatacaagataatagtgacataaaagtagtgccaagaagaaaagcaaagatcattagggattatggaaaacagatggcaggtgatgattgtgtggcaagtagacaggatgaggattagaacatggaaaagtttagtaaaacaccatatgtatgtttcaaggaaagctaagggatggttttatagacatcactatgaaagtactcatccgagaataagttcagaagtacacatcccactagggaatgcaaaattggtaataacaacatattggggtctacatacaggagaaagagactggcatttgggtcaaggagtctccatagaattgaggaaaaggagatatagcacacaattagaccctaacctagcagaccaactaattcatctgcattactttgattgtttttcagaatctgctataagaaatgccatattaggacatatagttagccctaggtgtgaatatcaagcaggacataacaaggtaggatctctacagtacttggcactaacagcattagtaagaccaagaaaaaagataaagccacctttgcctagtgttacaaaactgacagaggatagatggaacaagccccagaagaccaagggccacaaagggaaccatacaatgaatggacactagaacttttagaggagctcaagaatgaagctgttagacattttcctaggatatggctccatagcttagggcaacatatctatgaaacttatggagatacttgggcaggagtggaagccataataagaattctgcaacaactgctgtttattcatttcagaattgggtgtcaacatagcagaatagacattcttcgacgaaggagagcaagaaatggagccagtagatcctagactagagccctggaagcatccaggaagtcagcctaggactgcttgtaccaattgctattgtaaaaagtgttgctttcattgccaagtttgtttcataacaaaaggcttaggcatctcctatggcaggaagaagcggagacagcgacgaagagctcctcaagacagtcagactcatcaagtttctctatcaaagcagtaagtagtacatgtaatgcaatctttacaaatattagcagtagtagcattagtagtagcagcaataatagcaatagttgtgtggtccatagtattcatagaatataggaaaataagaagacaaaacaaaatagaaaggttgattgatagaataatagaaagagcagaagacagtggcaatgagagtgacggagatcaggaagaattatcagcacttgtggaaatggggcacgatgctccttgggatgttaatgatctgtaaagctgcagaaaatttgtgggtcacagtttattatggggtacctgtgtggaaagaagcaaccaccactctattttgtgcctcagatgctaaagcgtatgatacagaggtacataatgtttgggccacacatgcctgtgtacccacagaccccaacccacaagaagtagaactgaagaatgtgacagaaaattttaacatgtggaaaaataacatggtagaccaaatgcatgaggatataattagtttatgggatcaaagcctaaagccatgtgtaaaattaaccccactctgtgttactttaaattgcactgattatgggaatgatactaacaccaataatagtagtgctactaaccccactagtagtagcgggggaatggaggggagaggagaaataaaaaattgctctttcaatatcaccagaagcataagagataaagtgaagaaagaatatgcacttttttatagtcttgatgtaataccaataaaagatgataatactagctataggttgagaagttgtaacacctcagtcattacacaggcctgtccaaaggtatcctttgaaccaattcccatacattattgtgccccggctggttttgcgattctaaagtgtaatgataaaaagttcaatggaaaaggaccatgtacaaatgtcagcacagtacaatgtacacatggaattaggccagtagtatcaactcaactgctgttaaatggcagtctagcagaagaagaggtagtaattagatcagacaatttctcggacaatgctaaagtcataatagtacatctgaatgaatctgtagaaattaattgtacaagactcaacaacattacaaggagaagtatacatgtaggacatgtaggaccaggcagagcaatttatacaacaggaataataggaaaaataagacaagcacattgtaacattagtagagcaaaatggaataacactttaaaacagatagttacaaaattaagagaacaatttaagaataaaacaatagtctttaatcaatcctcaggaggggacccagaaattgtaatgcacagttttaattgtggaggggaatttttctactgtaattcaacacaactgtttaacagtacttggaatggtactgcatggtcaaataacactgaaggaaatgaaaatgacacaatcacactcccatgcagaataaaacaaattataaacatgtggcaggaagtaggaaaagcaatgtatgcacctcccatcagaggacaaattagatgttcatcaaatattacagggctgatattaacaagagatggtggtattaaccagaccaacaccaccgagattttcaggcctggaggaggagatatgaaggacaattggagaagtgaattatataaatataaagtagtaaaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcaaagagaaaaaagagcagtgggaataataggagctatgctccttgggttcttgggagcagcaggaagcactatgggcgcagcgtcaatgacgctgacggtacaggccagacaattattgtctggtatagtgcaacagcagaacaatttgctgagggctattgaggcgcaacagcatctgttgcacctcacagtctggggcatcaagcagctccaagcaagagtcctggctgtggaaagatacctaagggatcaacagctcctggggttttggggttgctctggaaaactcatttgcaccactgctgtgccttggaatactagttggagtaataaatctctgagtcagatttgggataacatgacctggatgcagtgggaaagggaaattgataattacacaagcttaatatacaacttaattgaagaatcgcaaaaccaacaagaaaagaatgaacaagagttattggaattagataactgggcaagtttgtggaattggtttagcataacaaattggctgtggtatataaaaatattcataatgatagtaggaggcttggtaggtttaagaatagtttttactgtactttctatagtaaatagagttaggcagggatactcaccattgtcgtttcagacgcgcctcccagccaggaggggacccgacaggcccgaaggaatcgaagaagaaggtggagagagagacagagacagatccggtcaattagtggatggattcttagcaattatctgggtcgacctgcggagcctgtgcctcttcagctaccaccgcttgagagacttactcttgattgtaacgaggattgtggaacttctgggacgcagggggtgggaagccctcaaatattggtggaatctcctacaatattggattcaggaactaaagaatagtgctgttagcttgctcaacgccacagccatagcagtagctgagggaactgatagggttatagaagtattacaaagagcttgtagagctattctccacatacctagaagaataagacagggcttagaaagggctttgcaataagatgggtggtaagtggtcaaaaagtagtaaaattggatggcctactgtaagggaaagaatgagaagagctgagccagcagcagatggggtgggagcagtatctcgagacctggaaaaacatggagcaatcacaagtagtaatacagcaactaacaatgctgattgtgcctggctagaagcacaagaggaggaggaggtgggttttccagtcagacctcaggtacctttaagaccaatgacttacaagggagcgttagatcttagccactttttaaaagaaaaggggggactggaagggctaatttggtcccagaaaagacaagacatccttgatttgtgggtccaccacacacaaggctacttccctgattggcagaactacacaccagggccagggatcagatatccactgacctttggttggtgcttcaagctagtaccagttgagccagagaaggtagaagaggccaatgaaggagagaacaacagattgttacaccctgtgagcctgcatgggatggaggacccggagaaagaagtgttagtatggaggtttgacagccgcctagtactccgtcacatggcccgagagctgcatccggagtactacaaggactgctgacactgagctttctacaagggactttccgctggggactttccagggaggcgtggcctgggcgggactggggagtggcgagccctcagatgctgcatataagcagctgctttttgcctgtactgggtctctcttgttagaccagatctgagcctgggagctctctggctaactagggaacccactgcttaagcctcaataaagcttgccttgagtgcttca

gggtctctcttgttagaccagatctgagcctgggagctctctggctaactagggaacccactgcttaagcctcaataaagcttgccttgagtgcttcaagtagtgtgtgcccgtctgttgtgtgactctgatagctagagatcccttcagaccaaatttagtcagtgtgaaaaatctctagcagtggcgcctgaacagggacttgaaagcgaaagagaaaccagagaagctctctcgacgcaggactcggcttgctgaagcgcgcacggcaagaggcgaggggacggcgactggtgagtacgccaaaattttgactagcggaggctagaaggagagagatgggtgcgagagcgtcgatattaagcgggggaggattagatagatgggaaaaaattcggttaaggccagggggaaagaaaaaatatagattaaaacatttagtatgggcaagcagggagctagaacgattcgcagtcaatcctggcctattagaaacatcagaaggttgtagacaaatactgggacaactacaaccagcccttcagacaggatcagaagaacttagatcattatataatacagtagcaaccctctattgtgtgcatcaaaagatagatgtaaaagacaccaaggaagctttagataagatagaggaagagcaaaacaaaagtaagaaaaaagcacagcaagcagcagctgacacaggaaatagcagccaggtcagccaaaattaccccatagtgcagaacatccaggggcaaatggtacatcaggccatatcacctagaactttaaatgcatgggtaaaagtagtagaagagaaggctttcagcccagaagtaatacccatgttttcagcattatcagaaggagccaccccacaagatttaaacaccatgctaaacacagtggggggacatcaagcagccatgcaaatgttaaaagagaccatcaatgaggaagctgcagaatgggatagattgcatccagtgcatgcagggcctcatccaccaggccagatgagagaaccaaggggaagtgacatagcaggaactactagtacccttcaggaacaaatagcatggatgacaaataatccacctatcccagtaggagaaatctataagagatggataatcctgggattaaataaaatagtaaggatgtatagccctaccagcattctggacataaaacaaggaccaaaggaaccctttagagactatgtagaccggttctataagactctaagagccgagcaagcttcacaggaggtaaaaaattggatgacagaaaccttgttggtccaaaatgcgaacccagattgtaagactattttaaaagcattgggaccagcagctacactagaagaaatgatgacagcatgtcagggagtgggaggacccggccataaagcaagagttttggcagaagcaatgagccaagtaacaaattcagctaccataatgatgcagaaaggcaattttaggaaccaaagaaaaattgttaagtgtttcaattgtggcaaagaagggcacatagccaaaaattgcagggcccctaggaaaaggggctgttggaaatgtggaaaggagggacaccaaatgaaagattgtactgagagacaggctaattttttagggaaaatctggccttcccacaggggaaggccagggaattttcctcagaacagactagagccaacagccccaccagccccaccagaagagagcttcaggtttggggaagagacaacaactccctctcagaagcaggagctgatagacaaggaactgtatccttcagcttccctcaaatcactctttggcaacgaccccttgtcacaataaagataggggggcaactaaaggaagctctattagatacaggagcagatgatacagtattagaagaaataaatttgccaggaagatggaaaccaaaaatgatagggggaattggaggttttatcaaagtaagacagtatgatcaaatactcgtagaaatctgtggacataaagctataggtacagtattagtaggacctacacctgtcaacataattggaagaaatctgttgactcagattggttgcactttaaattttcccattagtcctattgaaactgtaccagtaaaattaaagccaggaatggatggcccaaaagttaaacaatggccattgacagaagaaaaaataaaagcattagtagaaatctgtacagaaatggaaaaggaaggaaaaatttcaaaaatcgggcctgaaaatccatataatactccagtatttgccataaagaaaaaagacagtactaaatggagaaaattagtagatttcagagaacttaataagaaaactcaagacttctgggaagttcaattaggaataccacatcccgcagggttaaaaaagaaaaaatcagtaacagtactggatgtgggtgatgcatatttttcagttcccttagataaagaattcaggaagtacactgcatttaccatacctagtataaacaatgagacaccagggattagatatcagtacaatgtgcttccacagggatggaaaggatcaccagcaatattccaaagcagcatgacaaaaatcttagagccttttagaaaacaaaatccagacatagttatctatcaatacatggacgatttgtatgtaggatctgacttagaaatagggcagcatagaacaaaaatagaggaactgagacaacatctgttgaagtggggatttaccacaccagacaaaaaacatcagaaagaacctccattcctttggatgggttatgaactccatcctgataaatggacagtacagcctatagtgctgccagaaaaggacagctggactgtcaatgacatacagaagttagtgggaaaattgaattgggcaagtcagatttacccagggattaaagtaaagcaattatgtagactccttaggggaaccaaggcactaacagaagtaataccactaacaaaagaagcagagctagaactggcagaaaacagggaaattctaaaagaaccagtacatggagtgtattatgacccatcaaaagacttaatagcggaaatacagaagcaggggcaaggtcaatggacatatcaaatttatcaagagccatttaaaaatctgaaaacaggaaaatatgcaagaatgaggggtgcccacactaatgatgtaaaacaattaacagaggcagtgcaaaaaataaccacagaaagcatagtaatatggggaaagactcctaaatttaaactacccatacaaaaagaaacatgggaaacatggtggacagagtattggcaagccacctggattcctgagtgggagtttgtcaatacccctcccttagtaaaattatggtaccagttagagaaagaacccataataggagcagaaactttctatgtagatggggcagctaacagggagactaaattaggaaaagcaggatatgttactaacaaagggagacaaaaagttgtctccataactgacacaacaaatcagaagactgagttacaagcaattcttctagcattacaggattctggattagaagtaaacatagtaacagactcacaatatgcattaggaatcattcaagcacaaccagataaaagtgaatcagagatagtcagtcaaataatagagcagttaataaaaaaagaaaaggtctacctgacatgggtaccagcgcacaaaggaattggaggaaatgaacaagtagataaattagtcagtactggaatcaggaaagtactctttttagatggaatagataaagcccaagaagaacatgaaaaatatcacagtaattggagggcaatggctagtgattttaacctgccacctgtggtagcaaaagagatagtagccagctgtgataaatgtcagctaaaaggagaagccatgcatggacaagtagactgtagtccaggaatatggcaactagattgtacacatttagaaggaaaaattatcctggtagcagttcatgtagccagtggatatatagaagcagaagttattccagcagaaacagggcaggaaacagcatactttctcttaaaattagcaggaagatggccagtaaaaacagtacatacagacaatggcagcaatttcaccagtactacagttaaggccgcctgttggtgggcaggaatcaagcaggaatttggcattccctacaatccccaaagtcaaggagtagtagaatctataaataaagaattaaagaaagttataggacagataagagatcaggctgaacatcttaagacagcagtacaaatggcagtattcatccacaattttaaaagaaaaggggggattggggggtacagtgcaggggaaagaatagtagacataatagcaacagacatacaaactaaagaactacaaaaacaaattacaaaaattcaaaattttcgggtttattacagggacagcagagatccactttggaaaggaccagcaaagcttctctggaaaggtgaaggggcagtagtaatacaagataatagtgacataaaagtagtgccaagaagaaaagcaaagatcattagggattatggaaaacagatggcaggtgatgattgtgtggcaagtagacaggatgaggattagaacatggaaaagtttagtaaaacaccatatgtatgtttcaaggaaagctaagggatggttttatagacatcactatgaaagtactcatccgagaataagttcagaagtacacatcccactagggaatgcaaaattggtaataacaacatattggggtctacatacaggagaaagagactggcatttgggtcaaggagtctccatagaattgaggaaaaggagatatagcacacaattagaccctaacctagcagaccaactaattcatctgcattactttgattgtttttcagaatctgctataagaaatgccatattaggacatatagttagccctaggtgtgaatatcaagcaggacataacaaggtaggatctctacagtacttggcactaacagcattagtaagaccaagaaaaaagataaagccacctttgcctagtgttacaaaactgacagaggatagatggaacaagccccagaagaccaagggccacaaagggaaccatacaatgaatggacactagaacttttagaggagctcaagaatgaagctgttagacattttcctaggatatggctccatagcttagggcaacatatctatgaaacttatggagatacttgggcaggagtggaagccataataagaattctgcaacaactgctgtttattcatttcagaattgggtgtcaacatagcagaatagacattcttcgacgaaggagagcaagaaatggagccagtagatcctagactagagccctggaagcatccaggaagtcagcctaggactgcttgtaccaattgctattgtaaaaagtgttgctttcattgccaagtttgtttcataacaaaaggcttaggcatctcctatggcaggaagaagcggagacagcgacgaagagctcctcaagacagtcagactcatcaagtttctctatcaaagcagtaagtagtacatgtaatgcaatctttacaaatattagcagtagtagcattagtagtagcagcaataatagcaatagttgtgtggtccatagtattcatagaatataggaaaataagaagacaaaacaaaatagaaaggttgattgatagaataatagaaagagcagaagacagtggcaatgagagtgacggagatcaggaagaattatcagcacttgtggaaatggggcacgatgctccttgggatgttaatgatctgtaaagctgcagaaaatttgtgggtcacagtttattatggggtacctgtgtggaaagaagcaaccaccactctattttgtgcctcagatgctaaagcgtatgatacagaggtacataatgtttgggccacacatgcctgtgtacccacagaccccaacccacaagaagtagaactgaagaatgtgacagaaaattttaacatgtggaaaaataacatggtagaccaaatgcatgaggatataattagtttatgggatcaaagcctaaagccatgtgtaaaattaaccccactctgtgttactttaaattgcactgattatgggaatgatactaacaccaataatagtagtgctactaaccccactagtagtagcgggggaatggaggggagaggagaaataaaaaattgctctttcaatatcaccagaagcataagagataaagtgaagaaagaatatgcacttttttatagtcttgatgtaataccaataaaagatgataatactagctataggttgagaagttgtaacacctcagtcattacacaggcctgtccaaaggtatcctttgaaccaattcccatacattattgtgccccggctggttttgcgattctaaagtgtaatgataaaaagttcaatggaaaaggaccatgtacaaatgtcagcacagtacaatgtacacatggaattaggccagtagtatcaactcaactgctgttaaatggcagtctagcagaagaagaggtagtaattagatcagacaatttctcggacaatgctaaagtcataatagtacatctgaatgaatctgtagaaattaattgtacaagactcaacaacattacaaggagaagtatacatgtaggacatgtaggaccaggcagagcaatttatacaacaggaataataggaaaaataagacaagcacattgtaacattagtagagcaaaatggaataacactttaaaacagatagttacaaaattaagagaacaatttaagaataaaacaatagtctttaatcaatcctcaggaggggacccagaaattgtaatgcacagttttaattgtggaggggaatttttctactgtaattcaacacaactgtttaacagtacttggaatggtactgcatggtcaaataacactgaaggaaatgaaaatgacacaatcacactcccatgcagaataaaacaaattataaacatgtggcaggaagtaggaaaagcaatgtatgcacctcccatcagaggacaaattagatgttcatcaaatattacagggctgatattaacaagagatggtggtattaaccagaccaacaccaccgagattttcaggcctggaggaggagatatgaaggacaattggagaagtgaattatataaatataaagtagtaaaaattgaaccattaggagtagcacccaccaaggcaaagagaagagtggtgcaaagagaaaaaagagcagtgggaataataggagctatgctccttgggttcttgggagcagcaggaagcactatgggcgcagcgtcaatgacgctgacggtacaggccagacaattattgtctggtatagtgcaacagcagaacaatttgctgagggctattgaggcgcaacagcatctgttgcacctcacagtctggggcatcaagcagctccaagcaagagtcctggctgtggaaagatacctaagggatcaacagctcctggggttttggggttgctctggaaaactcatttgcaccactgctgtgccttggaatactagttggagtaataaatctctgagtcagatttgggataacatgacctggatgcagtgggaaagggaaattgataattacacaagcttaatatacaacttaattgaagaatcgcaaaaccaacaagaaaagaatgaacaagagttattggaattagataactgggcaagtttgtggaattggtttagcataacaaattggctgtggtatataaaaatattcataatgatagtaggaggcttggtaggtttaagaatagtttttactgtactttctatagtaaatagagttaggcagggatactcaccattgtcgtttcagacgcgcctcccagccaggaggggacccgacaggcccgaaggaatcgaagaagaaggtggagagagagacagagacagatccggtcaattagtggatggattcttagcaattatctgggtcgacctgcggagcctgtgcctcttcagctaccaccgcttgagagacttactcttgattgtaacgaggattgtggaacttctgggacgcagggggtgggaagccctcaaatattggtggaatctcctacaatattggattcaggaactaaagaatagtgctgttagcttgctcaacgccacagccatagcagtagctgagggaactgatagggttatagaagtattacaaagagcttgtagagctattctccacatacctagaagaataagacagggcttagaaagggctttgcaataagatgggtggtaagtggtcaaaaagtagtaaaattggatggcctactgtaagggaaagaatgagaagagctgagccagcagcagatggggtgggagcagtatctcgagacctggaaaaacatggagcaatcacaagtagtaatacagcaactaacaatgctgattgtgcctggctagaagcacaagaggaggaggaggtgggttttccagtcagacctcaggtacctttaagaccaatgacttacaagggagcgttagatcttagccactttttaaaagaaaaggggggactggaagggctaatttggtcccagaaaagacaagacatccttgatttgtgggtccaccacacacaaggctacttccctgattggcagaactacacaccagggccagggatcagatatccactgacctttggttggtgcttcaagctagtaccagttgagccagagaaggtagaagaggccaatgaaggagagaacaacagattgttacaccctgtgagcctgcatgggatggaggacccggagaaagaagtgttagtatggaggtttgacagccgcctagtactccgtcacatggcccgagagctgcatccggagtactacaaggactgctgacactgagctttctacaagggactttccgctggggactttccagggaggcgtggcctgggcgggactggggagtggcgagccctcagatgctgcatataagcagctgctttttgcctgtactgggtctctcttgttagaccagatctgagcctgggagctctctggctaactagggaacccactgcttaagcctcaataaagcttgccttgagtgcttca

Same "Sequence" - still different ...

We need to understand structure and function of proteins.

(Source: PDB)

Public Database content Experimentally determined protein structures (PDB)

214

1588

37'874

100

1,000

10,000

100,000

1,000,000

10,000,000

1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006

PDB

Public Database content Experimentally known protein structures (PDB)

100

1,000

10,000

100,000

1,000,000

10,000,000

1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006

SwissProt

PDB

Public Database content Annotated Protein Sequences: Swiss-Prot

100

1,000

10,000

100,000

1,000,000

10,000,000

1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006

TrEMBL

SwissProt

PDB

No experimentalstructure for mostprotein sequences

Public Database content Protein Sequences translated from DNA: trEMBL

(Sources: PDB, EBI, SIB)

The protein sequence contains all information needed to create a correctly folded protein (Anfinsen principle).Can we model protein structures from their protein sequences?

Many proteins fold spontaneously to their native structure Protein folding is relatively fast (nsec – sec) Chaperones speed up folding, but do not alter the structure

MNIFEMLRID EGLRLKIYKD TEGYYTIGIG HLLTKSPSLN AAKSELDKAI GRNCNGVITKDEAEKLFNQD VDAAVRGILR NAKLKPVYDS LDAVRRCALI NMVFQMGETG VAGFTNSLRMLQQKRWDEAA VNLAKSRWYN QTPNRAKRVI TTFRTGTWDA YKNL

Protein Folding

Comparative protein structure modelling

René Magritte. The Human Condition. 1935. Oil on canvas.

Known Structures(Templates)

Target Sequence Template Selection

Alignment Template - Target

Structure modeling

Structure Evaluation & Assessment

HomologyModel(s)

Comparative Protein Structure Modelling

Comparative Protein Structure Modelling

Why do we need automated expert systems for comparative protein modelling?

Too many new sequences, too many new structures

Objectivity and Reproducibility: remove individual human bias;

predictable reliability of results

Improve methods and algorithms

Easy access for “end users”

User emails ...

To: <Torsten.Schwede@isb-sib.ch>From: Karin Schwarz <xxxxxxx@gmx.de>

Dear Mr. Schwede,

I am looking for firms, which needs also models with a high from 168 cm. Do you need someone?

Best regards

K. Schwarz

ExPASY

Biozentrum, SIB (Basel) & NCI (ABBC)

PDB Database-> SMTL

SwissProt/TrEMBL

RCSB

EBI

NR / Blast NCBI

How to automate protein modeling?

Target Sequence

Known Structures(Templates)

Template Selection

Alignment Template - Target

Structure modeling

Structure Evaluation &Assessment

HomologyModel(s)

3D - Model requests:

2005: >148’000 requests

~ 400 models per work day~ one model every 4 minutes

SWISS-MODEL Server

1. M.C. Peitsch and C.V. Jongeneel (1993) Int. Immunol. 5, 233-2382. Peitsch MC (1995) Bio/Technology 13:658-660. 3. Guex N and Peitsch MC (1997) Electrophoresis 18:2714-2723.4. Schwede T, Kopp J, Guex N, Peitsch MC (2003) Nucleic Acids Research 31, 3381-3385.

SWISS-MODEL Workspace

Arnold K, Bordoli L, Kopp J, Schwede T (2006) Bioinformatics 22,195-201.

SWISS-MODEL Template Library

Arnold K, Bordoli L, Kopp J, Schwede T (2006) Bioinformatics 22,195-201.

[ http://www.expasy.org/spdbv/ ]

Collaboration withNicolas Guex (GSK)

DeepView - Swiss-PdbViewer

Guex N and Peitsch MC (1997) Electrophoresis 18:2714-2723.

SwissProt / TrEMBL

SWISS-MODELRepository

Oracle Control DB

Qualityok?

PDB/SMTL

Sequence updates

Template updates

SWISS-MODELServer

UpdateModel?

SWISS-MODELRepository

mySQL DB / WEB

Image Rendering Server

Coordinate Repository Server

Computational Services e.g. Anolea quality control

Reverse Proxy Services

CRC64

SWISS-MODEL Repository

Kopp J, and Schwede T (2004). Nucleic Acids Research 32 , D230-D234.

SWISS-MODEL Repository

Kopp J, and Schwede T (2006). Nucleic Acids Research 34 , D315-D318.

SWISS-MODEL Repository

Kopp J, and Schwede T (2006). Nucleic Acids Research 34 , D315-D318.

SWISS-MODEL Repository

Kopp J, and Schwede T (2006). Nucleic Acids Research 34 , D315-D318.

Evaluation of Model Accuracy

SIV Model based on: 1BL3 (C) HIV-1 Integrase core domainExperimental structure: 1C6V (C) SIV Integrase core domainSeq. Identity: 61 %

“... a model must be wrong, in

some respects -- else it would be the thing itself. The trick is to see ... where it is right.”

Evaluation of model accuracy

Henry A. Bent"Uses (and Abuses) of Models in Teaching Chemistry," J. Chem. Ed. 1984 61, 774.

Evaluation of Model Accuracy

CASPCommunity Wide Experiment on the Critical Assessment of Techniques for Protein Structure Predictionhttp://PredictionCenter.org

EVA Evaluation of Automatic protein structure prediction http://eva.compbio.ucsf.edu/~eva/

(Koh et al. (2003) Nucleic Acids Res. 31, 3311-5 )

3D - Crunch ExperimentVery Large Scale Protein Modelling Project (1998) http://www.expasy.org/swissmod/SM_LikelyPrecision.html

Weekly PDB released target sequencesMNIFEMLRID EGLRLKIYKD TEGYYTIGIG HLLTKSPSLN AAKSELDKAI GRNCNGVITK

EVA Server Prediction Servers

e.g. SWISS-MODEL

1

Evaluation of automated protein structure prediction

(Koh et al. (2003) Nucleic Acids Res. 31, 3311-5 )

2 Predicted structure

Evaluation of prediction accuracy

3

Does the model have the correct fold? What would have been the best template? What would have been the best alignment? How difficult was the modeling?

Alignment accuracy Overall accuracy (RMSD)

core regions loop regions side chain rotamer

Stereo-chemical quality of the model

MNIFEMLRID EGLRLKIYKD TEGYYTIGIG HLLTKSPSLN AAKSELDKAI GRNCNGVITK

Evaluation of Automated protein structure prediction

[ Data source: EVA-CM http://cubic.bioc.columbia.edu/eva/ ]

The analysis of ~1 year of models for all PDB

released structures is necessary for a

statistically relevant comparison of modelling

methods.

Evaluation of 246 weekly PDB releases (20'108 models)

Evaluation of Automated protein structure prediction

Evaluation of 246 weekly PDB releases (20'108 models)

[ Data source: EVA-CM http://cubic.bioc.columbia.edu/eva/ ]

SWISS-MODEL has the lowest

cumulative average global RMSD of the

servers in the comparison.

Evaluation of Automated protein structure prediction

[ Data source: EVA-CM http://cubic.bioc.columbia.edu/eva/ ]

The lower RMSD of SWISS-

MODEL is related to a

lower coverage in sequence

space.

Evaluation of 246 weekly PDB releases (20'108 models)

Save Zone

TwilightZone

MidnightZone

Evaluation of Model Accuracy

[ Data source: EVA-CM http://cubic.bioc.columbia.edu/eva/ ]

Applications of comparative modelling

Possible applications of comparative models depend on the expected accuracy.

(Kopp & Schwede, Pharmacogenomics, 2004 )

Application Examples

Structural Assessment of Sequence VariationsComparative modeling allows for detailed structure-based assessment of sequence variations. Mutations, ns-cSNPs, alternative splicing, iso-forms and other sequence variations may be responsible for functional variations and involved in rare inherited diseases, individual differences in drug response, and susceptibility for common diseases.

(Wattenhofer, et. al. J. Mol. Med. 2002 )

Applications:

Rational design of Functional MutationsComparative modeling allows for designing specific site directed mutations

to study functional role of individual residues or structural features.

Example: Design of partial and complete deletion mutations of the plug

domain of Sec61p to study its functional role. Conclusion: The plug domain

of Sec61p is non-essential, but influences topogenesis and Sec61 assembly.

Junne, Schwede, Goder & Spiess (2006) Molecular Cell, in press

Application: Models in structure based drug discovery

Can homology models be used in structure based drug discovery when no experimental protein structures are available?

How do errors and inaccuracies of the homology models affect the subsequent molecular modeling of protein-ligand interaction?

Estimating relative ligand binding free energies using MD-GBSA

500 ps MD Simulation for conformational sampling (MM-GBSA)∆Gbind = < ∆Evacuo > + < ∆Gdesolv > - < T∆S >

Collaboration with Markus Meuwly (Computational Chemistry, Uni Basel) & Vincent Zoete (SIB Lausanne)

Thorsteinsdottir HB, Schwede T, Zoete V, and Meuwly M (2006). Proteins (in press).

Example: 16 HIV-I protease inhibitor complexes Validation: Correlation between experimental and

calculated relative binding free energies Application: Systematic analysis of the influence of typical

modeling errors.

Application: Models in structure based drug discovery

Reference1HVI

relative Gcalculated

Reference Model:All ligands computed in 1HVI as reference structure

HM based onEIAV

Rotamer model

relative Gcalculatedrelative Gcalculated

Twilight Zone Model:based on Equine infectious anemia virus protease (1FMB) sharing 32% seq. id.RMSD (5 Å of ligand) 1.30 Å

SCWRL Rotamer Model:Rotamers of reference structure remodelled using SCWRL3.0.1

RMSD (5 Å of ligand) 1.26 Å1 SCWRL3.0 (A. A. Canutescu, A. A. Shelenkov, and R. L. Dunbrack, Jr. Protein Science 12, 2001-2014 (2003). Thorsteinsdottir HB, Schwede T, Zoete V, and Meuwly M (2006). Proteins (in press).

Summary and Outlook

Summary and outlook

Today's Bioinformatics view is still largely (DNA)- sequence centric. Understanding macromolecular function in detail requires knowledge of its 3D structure.

10 years ago, for the vast the majority of proteins no information about its 3-dimensional structure was available.

Today, structural genomics and comparative modelling are complementing each other in exploring the structural space. Within the next decade, 3D information will become available for the majority of all globular protein domains.

> 90 % of this structural information will be based on comparative models.

SWISS-MODEL aims at providing a fully integrated protein-centric view of all available structural information on a given protein.

SWISS-MODEL is accessible freely at Expasy:

SWISS-MODEL

SWISS-MODEL Server: http://swissmodel.expasy.org

DeepView (Swiss-PdbViewer) http://www.expasy.org/spdbv/

SWISS-MODEL Workspace: http://swissmodel.expasy.org/workspace/

SWISS-MODEL Repository: http://swissmodel.expasy.org/repository/

Biozentrum & SIB BaselHólmfríður B. ÞorsteinsdóttirLorenza BordoliJürgen KoppMichael PodvinecJames BatteyKonstantin ArnoldRainer PöhlmannRoger JenniRobert GaisbauerMihaela ZavolanMartin Spiess

University of BaselMarkus Meuwly

Novartis BaselManuel Peitsch

SIB - Swiss Institute of Bioinformatics (LS & GE) Amos BairochElisabeth GasteigerErnest FeytmansOlivier MichielinVincent ZoeteVictor JongeneelJacques Rougemont

NCI FrederickJack CollinsKarol Miaskiweicz Robert W. Lebherz

GSK R&DNicolas GuexAlexander Diemand Financial support:

EBI - European Bioinformatics InstituteKim HenrickRolf ApweilerNicola MoulderUjjwal Das

Pontificia Universidad Católica de Chile Francisco Melo

Acknowledgements

Biozentrum & SIB BaselHólmfríður B. ÞorsteinsdóttirLorenza Bordoli Jürgen KoppMichael PodvinecJames BatteyKonstantin ArnoldRainer PöhlmannRoger JenniRobert GaisbauerMihaela ZavolanMartin Spiess

University of BaselMarkus Meuwly

Novartis BaselManuel Peitsch

SIB - Swiss Institute of Bioinformatics (LS & GE) Amos BairochElisabeth GasteigerErnest FeytmansOlivier MichielinVincent ZoeteVictor JongeneelJacques Rougemont

NCI FrederickJack CollinsKarol Miaskiweicz Robert W. Lebherz

GSK R&DNicolas Guex Alexander Diemand Financial support:

EBI - European Bioinformatics InstituteKim HenrickRolf ApweilerNicola MoulderUjjwal Das

Pontificia Universidad Católica de Chile Francisco Melo

Acknowledgements