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Applications of Homology Modeling Hanka Venselaar

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This seminar…. Homology Modeling… Why? What? When? How? And a few real world examples….

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Homology modeling Example: by 80 residues 30% identity sufficient # residues % identity * * Actually, modelling is possible, but we cannot get an alignment… O

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Homology modeling in short… Prediction of structure based upon a highly similar structure Add sidechains, Molecular Dynamics simulation on model Unknown structure NSDSECPLSHDG || || | || NSYPGCPSSYDG Alignment of model and template sequence Known structure Back bone copied Copy backbone and conserved residues Model!

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The 8 steps of Homology modeling

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1: Template recognition and initial alignment

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BLAST your sequence against PDB Best hit normally template Initial alignment NSDSECPLSHDGYCLHDGVC || || | ||||| ||| NSYPGCPSSYDGYCLNGGVC

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1: Template recognition and initial alignment 2: Alignment correction

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Functional residues conserved Use multiple sequence alignments Deletions shift gaps CPISRTGASIFRCW CPISRTA---FRCW CPISRT---AFRCW CPISRTAAS-FRCW CPISRTG-SMFRCW CPISRTA--TFRCW CPISRTAASHFRCW CPISRTGASIFRCW CPISRTA---FRCW Both are possible Multipe sequence alignment Correct alignment Sequence with known structure Your sequence

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2: Alignment correction Core residues conserved Use multiple sequence alignments Deletions in your sequence shift gaps Known structure FDICRLPGSAEAV Model FNVCRMP---EAI Model FNVCR---MPEAI S G P L A E R C IV C R M P E V C R M P E Correct alignment F-D- -A-V

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1: Template recognition and initial alignment 2: Alignment correction 3: Backbone generation

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Making the model…. Copy backbone of template to model Make deletions as discussed (Keep conserved residues)

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1: Template recognition and initial alignment 2: Alignment correction 3: Backbone generation 4: Loop modeling

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Known structure GVCMYIEA---LDKYACNC Your sequence GECFMVKDLSNPSRYLCKC Loop library, try different options

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1: Template recognition and initial alignment 2: Alignment correction 3: Backbone generation 4: Loop modeling 5: Sidechain modeling

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5: Side-chain modeling Several options Libraries of preferred rotamers based upon backbone conformation

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1: Template recognition and initial alignment 2: Alignment correction 3: Backbone generation 4: Loop modeling 5: Sidechain modeling 6: Model optimization

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Molecular dynamics simulation Remove big errors Structure moves to lowest energy conformation

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1: Template recognition and initial alignment 2: Alignment correction 3: Backbone generation 4: Loop modeling 5: Sidechain modeling 6: Model optimization 7: Model validation

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7: Model Validation Second opinion by PDBreport /WHATIF Errors in active site? new alignment/ template No errors? Model!

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1: Template recognition and initial alignment 2: Alignment correction 3: Backbone generation 4: Loop modeling 5: Sidechain modeling 6: Model optimization 7: Model validation 8: Iteration

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Model! 1: Template recognition and initial alignment 2: Alignment correction 3: Backbone generation 4: Loop modeling 5: Sidechain modeling 6: Model optimization 7: Model validation 8: Iteration

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8 steps of homology modeling 1: Template recognition and initial alignment 2: Alignment correction 3: Backbone generation 4: Loop modeling 5: Side-chain modeling 6: Model optimization 7: Model validation 8: Iteration Alignment Modeling Correction

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Homology Modeling… What? Prediction of an unknown structure based on an homologous and known structure Why? To answer biological and medical questions when the “real” structure is unknown When? A template with enough identity must be available How? 8 Steps To conclude….

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And now…. After the next seminar go to the course website: Thanks to Hanka Venselaar for making nearly all slides in this seminar.

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