Fold Recognition

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Fold Recognition

• Ole Lund,
• Associate professor,
• CBS

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Fold recognition

• Find template for modeling
• 1st step in comparative modeling
• Can be used to predict function

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Template identification

• Search with sequence
• Blast against proteins with known structure
• Psi-Blast against all proteins
• Fold recognition methods
• Use biological information
• Functional annotation in databases
• Active site/motifs

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Blast derivatives PDB-BLAST

• Procedure
• Build sequence profile by iterative PSI-BLAST
  search against a sequence database
• Use profile to search database of proteins with
  known structure
• Advantage
• Makes sure hid to protein with known structure is
  not hidden behind a lot of hits to other proteins

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BLAST derivatives Transitive BLAST

• Procedure
• Find homologues to query (your) sequence
• Find homologues to these homologues
• Etc.
• Can be implemented with e.g. BLAST or PSI-BLAST
• Also known as Intermediate Sequence Search (ISS)

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CASP

• CASP
• Critical Assessment of Structure Predictions
• Every second year
• Sequences from about-to-be-solved-structures are
  given to groups who submit their predictions
  before the structure is published
• Modelers make prediction
• Meeting in Asilomar where correct answers are
  revealed

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Target difficulty

• CM Comparative (homology) modeling
• CM/FR not PSI-BLAST (but ISS) findable
• FR(H) Homologous fold recognition
• FR(A) Analogous fold recognition
• NF/FR Partly New fold
• NF New Fold (used to be called Ab Initio -from
  first principles- prediction)

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CASP5 overview
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Successful fold recognition groups at CASP5

• 3D-Jury (Leszek Rychlewski)
• 3D-CAM (Krzysztof Ginalski)
• Template recombination (Paul Bates)
• HMAP (Barry Honig)
• PROSPECT (Ying Xu)
• ATOME (Gilles Labesse)

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Barry Honig
Abstract

• Sequencestructure profile-profile based
  alignment
• Database of template profiles
• Multiple structure alignment
• Sequence based profiles
• Position specific gap penalties derived from
  secondary structure
• Calibration to estimate statistical significance
• Query profile
• Sequence based profile
• Predicted secondary structure (consensus between
  PSI-PRED,PHD,JNET)

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Ying Xu
Abstract

• PROSPECToptimal alignments for a given energy
  function with any combination of the following
  terms
• mutation energy (including position-specific
  score matrix derived from multiple-sequence
  alignments),
• singleton energy (including matching scores to
  the predicted secondary structures),
• pairwise contact potential
• alignment gap penalties.

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3D-Jury (Rychlewski)

• Inspired by Ab initio modeling methods
• Average of frequently obtained low energy
  structures is often closer to the native
  structure than the lowest energy structure
• Find most abundant high scoring models
• Use output from a set of servers
• Superimpose all pairs of structures
• Similarity score Sij of Ca pairs within 3.5Å
  (if gt40else Sij0)
• 3D-Jury score SiSij/(N1)
• Similar methods developed by A Elofsson (Pcons)
  and D Fischer (3D shotgun)

Rychlewski.doc
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3D-CAM (Krzysztof Ginalski)
Ginalski.doc

• 3D-Consensus Alignment Method
• Structural alignment for all members of fold from
  FSSP
• Conservation of specific residues and contacts
• responsible for maintaining tertiary structure
• critical for substrate binding and/or catalysis
• Find homologues with iterative PSI-BLAST
• Align with ClustalW identify conserved residues
• Structural integrity of alignments
• Manual realignment
• Fold recognition for homologues
• Modelling
• Verification
• Visually
• Computationally (Verify3D, ProsaII, WHAT_CHECK)

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Paul A Bates - In Silico Recombination of
Templates, Alignments and Models
Abstract

• Problems
• Models rarely better than templates
• Manual intervention have marginal effect
• Possible solution
• Recombination of models

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Paul A Bates Modelling Procedure
Abstract

• Define domains
• Make models (FAMS/Pmodeller/EsyPred3D)
• Manual inspection/correction of alignments
• Alignment of annotated residues (PFAM)
• Preferably use alignment with gt2 bits/aa
• Select pair of models
• Superimpose
• Crossover or mutate (average coordinates)
• Select best proportion
• Contact pair potentials
• Solvation energies (calculated from solvent
  accessible area)
• Convergence
• Minimization and final refinements

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Gilles Labesse
Abstract

• Meta Server
• 3D-PSSM, PDB-BLAST, FUGUE, GenTHREADER, SAM-T99,
  JPRED-2
• Tool for Incremental Threading optimization
  (T.I.T.O.)
• Consensus ranking

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LiveBench

• The Live Bench Project is a continuous
  benchmarking program. Every week sequences of
  newly released PDB proteins are being submitted
  to participating fold recognition servers. The
  results are collected and continuous evaluated
  using automated model assessment programs. A
  summary of the results is produced after several
  months of data collection. The servers must delay
  the updating of their structural template
  libraries by one week to participate.

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Meta Server
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Meta Server
http//bioinfo.pl/meta/target.pl?id7296
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Score
wrong
correct
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Best servers?

• FFA3
• 3DS5
• INBG
• SHUM
• 3DPS
• 3DS3
• FUG3
• SHGU
• FUG2
• PCO2
• PRO2
• MGTH
• SFPP
• PMO3

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Links to fold recognition servers

• Databases of links
• http//bioinfo.pl/meta/servers.html
• http//mmtsb.scripps.edu/cgi-bin/renderrelres?prot
  model
• Meta server
• http//bioinfo.pl/meta/ (Example
  http//bioinfo.pl/meta/target.pl?id7296 )
• 3DPSSM good graphical output
• http//www.sbg.bio.ic.ac.uk/servers/3dpssm/
• GenTHREADER
• http//bioinf.cs.ucl.ac.uk/psipred/
• FUGUE2
• http//www-cryst.bioc.cam.ac.uk/fugue/prfsearch.h
  tml
• SAM
• http//www.cse.ucsc.edu/research/compbio/HMM-apps/
  T99-query.html
• FOLD
• http//fold.doe-mbi.ucla.edu/
• FFAS/PDBBLAST
• http//bioinformatics.burnham-inst.org/