09- allmodel

09- allmodel - Part 1: Comparative or Homology Modelling...

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Part 1: Comparative or Homology Modelling • Similar sequence similar structure • Requires reasonably close homologues • “within modelling distance” • the higher the similarity the better • Better with more templates • Good for secondary structural elements • Poor (difficult) for loops and distortions • Can be automated Principles The structure is determined by the sequence Some proteins fold spontaneously into a structure Others need chaperones (helper proteins) If we know the sequence we should know the structure Not possible at the moment! Some structure dependent on conditions Structure is more stable (changes slower) than Sequence Similar sequences will have similar folds Distantly related sequences can have similar structures h h h h h h h h h h h Structure is more stable than sequence Modelling Steps 1. Template recognition and alignment 2.Alignment correction 3.Backbone generation 4.Loop modelling 5.Side-chain modelling 6.Model optimisation 7. Model validation
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Modelling Steps In this example we model one domain of a two domain protein Finding a similar sequence A Blast/Fasta search of the PDB Find a sequence of known structure similar to yours Do the alignment with dynamic programming Good for relatively high similarity Search protein family databases Get multiple sequence alignments Do pattern searches Look for characteristic patterns in your sequence Search functional annotations if know something about sequence Similar function Similar structure Similar Sequence How Similar? • > 30% sequence identity • over 100 residues • structures are similar • 10 – 30% identity • Twilight Zone • May or may not be similar • Random sequences 6% - 10% identity Modelling Distance We must be confident that our protein has the same structure as the template(s) we want to use.
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Twilight Zone - Rost, B; Protein Eng, 12:85, 1999 Identical Residues Similar Residues Homologues Non-homologous Similar sequence / similar structure? Virtually guaranteed for longer sequences at 30% identity Not the case for shorter sequences 50% identity over ~ 35 residues does not mean similar structure Beware high levels of similarity in short sequences Short sequences can have several structures Sustained similarity over a longer run of amino acids needed Correcting an Alignment Areas of low identity difficult to align Use multiple sequences Check for unusual residues like a charged residue where rest are hydrophobic Very difficult to place start and end of indels Compare alignment to structure excessively large gaps in 3D space due to alignment know where hydrophobic core is in template -LTLTLTLT- | | | | TYTYTYTYTY | | | | | -YAYAYAYAY Pathological Sequence Alignment The alignment is unresolvable until the third sequence is added.
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09- allmodel - Part 1: Comparative or Homology Modelling...

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