Mathematical Challenges in Protein Motif Recognition

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Mathematical Challenges in Protein Motif
Recognition Bonnie Berger MIT
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Approaches to Structural Motif Recognition
Alignments Multiple alignments HMMs
Threading Profile methods (1D, 3D)
Statistical methods
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Structural Motif Recognition
1) Collect a database of positive examples of a
motif (e.g., coiled coil, beta helix). 2) Devise
a method to determine if an unknown sequence
folds as the motif or not. 3) Verification in lab.
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Our Coiled-Coil Programs

• PairCoil Berger, Wilson, Wolf, Tonchev, Milla,
  Kim,1995
• predicts 2-stranded CCs
• http//theory.lcs.mit.edu/paircoil
• MultiCoil Wolf, Kim, Berger, 1997
• predicts 3-stranded CCs
• http//theory.lcs.mit.edu/multicoil
• LearnCoil-Histidine Kinase Singh, Berger, Kim,
  Berger, Cochran, 1998
• predicts CCs in histidine kinase linker domains
• http//theory.lcs.mit.edu/learncoil
• LearnCoil-VMF Singh, Berger, Kim, 1999
• predicts CCs in viral membrane fusion proteins
• http//theory.lcs.mit.edu/learncoil-vmf

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Long Distance Correlations
In beta structures, amino acids close in the
folded 3D structure may be far away in the linear
sequence
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Biological Importance of Beta Helices

• Surface proteins in human infectious disease
• virulence factors (plants, too)
• adhesins
• toxins
• allergens
• Amyloid fibrils (e.g., Alzheimers, Creutzfeld
  Jakob (Mad Cow) disease)
• Potential new materials

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What is Known

• Solved beta-helix structures
• 12 structures in PDB in 7 different SCOP families
• Related work
• ID profile of pectate lyase (Heffron et al. 98)
• HMM (e.g., HMMER)
• Threading (e.g., 3D-PSSM)

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Key Databases
Solved structures Protein Data Bank (PDB) (100s
of non-redundant structures) www.rcsb.org/pdb/
Sequence databases Genbank (100s of thousands
of protein sequences) www.ncbi.nlm.nih.gov/Genban
k/GenbankSearch.html SWISSPROT (10s of
thousands of protein sequences) www.ebi.ac.uk/swi
ssprot
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BetaWrap Program
Bradley, Cowen, Menke, King, Berger RECOMB 2001

• Performance
• On PDB no false positives no false negatives.
• Recognizes beta helices in PDB across SCOP
  families in cross-validation.
• Recognizes many new potential beta helices.
• Runs in linear time (5 min. on SWISS-PROT).

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BetaWrap Program

• Histogram of protein scores for
• beta helices not in database (12 proteins)
• non-beta helices in PDB (1346 proteins )

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Single Rung of a Beta Helix
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3D Pairwise Correlations

Stacking residues in adjacent beta-strands
exhibit strong correlations Residues in the T2
turn have special correlations (Asparagine
ladder, aliphatic stacking)
B1
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3D Pairwise Correlations


Stacking residues in adjacent beta-strands
exhibit strong correlations Residues in the T2
turn have special correlations (Asparagine
ladder, aliphatic stacking)
B1
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Question but how can we find these correlations
which are a variable distance apart in sequence?
Tailspike, 63 residue turn
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Finding Candidate Wraps

• Assume we have the correct locations of a
• single T2 turn (fixed B2 B3).

Candidate Rung
B3
T2
B2

• Generate the 5 best-scoring candidates for the
  next rung.

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Scoring Candidate Wraps (rung-to-rung)

Similar to probabilistic framework plus

• Pairwise probabilities taken
• from amphipathic
• beta (not beta helix)
• structures in PDB.
• Additional stacking bonuses
• on internal pairs.
• Incorporates distribution on
• turn lengths.

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Scoring Candidate Wraps (5 rungs)

• Iterate out to 5 rungs generating candidate
  wraps

• Score each wrap
• - sum the rung-to-rung scores
• - B1 correlations filter
• - screen for alpha-helical content

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Potential Beta Helices

• Toxins
• Vaculating cytotoxin from the human gastric
  pathogen H. pylori
• Toxin B from the enterohemorrhagic E. coli
  strain O157H7
• Allergens
• Antigen AMB A II, major allergen from A.
  artemisiifolia (ragweed)
• Major pollen allergen CRY J II, from C. japonica
  (Japanese cedar)
• Adhesins
• AIDA-I, involved in diffuse adherence of
  diarrheagenic E. coli
• Other cell surface proteins
• Outer membrane protein B from Rickettsia
  japonica
• Putative outer membrane protein F from Chlamydia
  trachomatis
• Toxin-like outer membrane protein from
  Helicobacter pylori

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The Problem

• Given an amino acid residue subsequence, does it
  fold as a coiled coil? A beta helix?
• Very difficult
• peptide synthesis (1-2 months)
• X-ray crystallization, NMR (gt1 year)
• molecular dynamics
• Our goal predict folded structure based on a
  template of positive examples.

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Collaborators
Math / CS Mona Singh Ethan Wolf Phil Bradley
Lenore Cowen Matt Menke David Wilson Theo Tonchev
Biologists Peter S. Kim Jonathan King Andrea
Cochran James Berger Mari Milla