Bioinformatics of Protein Structure

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Bioinformatics of Protein Structure
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Protein structures often characterized by
secondary structure content

• All a
• All b
• a/b
• ab
• There are tools available (for instance at
  www.expasy.ch that will allow one to predict
  secondary structure from sequence data

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Sequence/structure

• All a-proteins begin to reveal sequence/structure
  relationship
• Coiled-coil proteins exhibit periodicity with
  hydrophobic residues
• Observe hydrophobic moments in membrane proteins

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1/4 of all predicted proteins in a genome are
membrane proteins
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A different periodicity in b-structures
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Common structures found in b structures

• Barrels
• Propellers
• Greek key
• Jelly roll (Contains one Greek key)
• Helix

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Barrels anti-parallel sheets
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Anti-parallel structures exhibit every other
amino acid periodicity
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Propellers

• Variable number of propeller blades

http//info.bio.cmu.edu/courses/03231/ProtStruc/b-
props.htm
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Quaternary structure of neuraminidase
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Looking for active sites
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g-crystallin has two domains with identical
topology

• Protein evolution
• motif duplication and
• fusion

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Three sheet b-helix Toblerone
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Protein structures containing a and b

• Distinction between a/b and a b
• a/b - Mainly parallel beta sheets
  (beta-alpha-beta units)
• a b - Mainly antiparallel beta sheets
  (segregated alpha and beta regions)

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a/b
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Interspersed a and b
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Generally, a tight hydrophobic core found in a/b
barrels
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How many folds are there?
Proteins have a common fold if they have the
same major secondary structures in the same
arrangement and with the same topological
connections.
To date we know 26,000 protein
structures Within this dataset, 945 folds are
recognized
http//scop.mrc-lmb.cam.ac.uk/scop/
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How many non-folds are there?

• http//www.scripps.edu/news/press/013102.html
• 30-40 of human genome encodes for unstructured
  native proteins

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Transition to structural classifications

• Several useful databases link sequence analysis
  and protein structure information
• Since structure is more highly conserved than
  sequence during evolution, structural alignment
  algorithms and classifications enable more
  distant evolutionary relatives to be identified.
• CATH and SCOP are two databases that organize
  protein structures, each containing 950-1400
  protein superfamilies

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Structural Alignments

• Various algorithms allow structure vs. structure
  comparisons
• VAST, DALI
• CATH (http//www.biochem.ucl.ac.uk/bsm/cath/)
  also has SSAP and GRATH (one computationally
  intensive, one not)
• Sequence similarity to structural families for
  modeling often extracted using PSI-BLAST
  (Gene3D)

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Comparison of sequence and structure alignments
1 Taylor WR, Orengo CA, 1989, Protein structure
alignment. J Mol Biol 2081-224 Mueller L,
2003, Protein structure alignment. Paper
presentations 27.51630h
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Multiple structural alignments

• CORA from CATH (where?)
• MultiProt - http//bioinfo3d.cs.tau.ac.il/MultiPro
  t/
• DMAPS (pre-calculated) http//dmaps.sdsc.edu/
• CE-MC - http//cemc.sdsc.edu/
• Others?

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CATH

• http//cathwww.biochem.ucl.ac.uk/latest/
• Classification Scheme Class, Architecture,
  Topology and Homology
• Class secondary structure composition and
  packing
• Architecture orientation of secondary
  structures in 3D, regardless of connectivity
• Topology both orientation and connectivity of
  secondary structure is accounted for
• Homologous superfamily grouped based on whether
  an evolutionary relationship exists (clustered at
  different levels of sequence ID)

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CATH hierarchy

• Structural alignments
• To homologous super-
• Family, then sequence
• Alignments for sequence
• Family, and then domains.

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Protein structure predictions

• Identifying similar protein structures using only
  amino acid sequence
• Modeling an amino acid sequence onto a known
  protein structure
• Ab initio protein structure prediction

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Test sequence

• gtrsp2570
• MTLDGKTIAILIAPRGTEDVEYVRPKEALTQATVVTVSLEPGEAQTVNGD
  LDPGATHRVDRTFADVSADAFDGLVIPGGTVGADKIRSSEEAVAFVRGFV
  SAGKPVAAICHGPWALVEADVLKGREVTSYPSLATDIRNAGGRWVDREVV
  VDSGLVTSRKPDDLDAFCAKMIEEFAEGVHDGQRRSA

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SCOP database

• Classification scheme Class, Fold, Superfamily,
  and Family,
• Class Type and organization of secondary
  structure
• Fold Share common core structure, same
  secondary structure elements in the same
  arrangement with the same topological connections
• Superfamily share very common structure and
  function
• Family protein domains share a clear common
  evolutionary origin as evidenced by sequence
  identity or similar structure/function

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HMMs are useful at SCOP

• For instance, SCOP (http//scop.mrc-lmb.cam.ac.uk/
  scop/) HMMs are derived from the PDB databank at
  www.rcsb.org
• Identify sequence signatures for specific domains

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Modeling protein structure based on homology

• SWISS-MODEL
• http//swissmodel.expasy.org/
• Using first approach mode, submit test sequence,
  and use your email
• PSI-Blast identifies the most similar sequence
  with a protein structure, and SWISS-MODEL wraps
  your input sequence around it
• Note you can also specify which structure you
  would like your sequence to wrap around

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Ab initio predictions

• Protein folding is a complex problem

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Ab initio attempts

• Based on Ramachandran plot probabilities
• Measure interatomic
• Interactions has
• worked for small proteins
• lt85 aa, which appear to
• Favor H-bonds and van
• Der Waal and ignore
• Electrostatic interactions