Detecting distant homologies among protein sequences by comparison of profile hidden Markov models

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• Detecting distant homologies among protein
  sequences by comparison of profile hidden Markov
  models
• Martin Madera
• Department of Computer Science
• University of Bristol

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What's a protein? (1/2)?
- linear polymer of amino-acids - protein
sequence string over alphabet of 20 amino-acids
stored in the DNA
sequence of its gene
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What's a protein? (2/2)?
all atoms
just backbone
cartoon
- proteins fold up into complex 3D structures
- structure functionally important, conserved
during evolution sequences diverge rapidly
- but solving structure experimentally hard, DNA
sequencing easy
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• The problem
• Find if proteins are related
  (homologous)?
• from their sequences alone
• Why?
• Homologs have similar structures and
• perform similar functions

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A simple approach
?
MLDQQTINIIKATVPVLKEHGVTITTTFYKNLFAKHPEVRPLFDMGRQES
LEQPKALAM TVLAAAQNIENLPAILPAVKKIAVKHCQAGVAAAHYPIVG
QELLGAIKEVLGDAATDDIL DAWGKAYGVIADVLYAQAVE
PIVDSGSVSPLSDAEKNKIRAAWDLVYKDYEKTGVDILVKFFTGTPAAQA
FFPKFKGLT TADDLKQSSDVRWHAERIINAVNDAVKSMDDTEKMSMKLK
ELSIKHAQSFYVDRQYF AGIIA
- take two sequences - calculate least number of
mutations required to turn one into the other -
compare to numbers for random sequences -
estimate level of significance
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Profiles of protein sequences
... model a family of related proteins
multiple sequence alignment
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Profile hidden Markov models (HMMs)?
deletes
inserts
matches
- stochastic machines that emit sequences - each
state emission probabilities transition
probabilities among states
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The traditional paradigm
?
MLDQQTINIIKATVPVLKEHGVTITTTFYKNLFAKHPEVRPLFDMGRQES
LEQPKALAM TVLAAAQNIENLPAILPAVKKIAVKHCQAGVAAAHYPIVG
QELLGAIKEVLGDAATDDIL DAWGKAYGVIADVLYAQAVE
unknown sequence s
HMM of a known family F
- calculate emission probability P(sHMM), -
compare to null probability P(sNULL), -
calibrate, estimate probability that s belongs to
F
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An obvious generalization?
?
collect similar unknown sequences, build HMM of
an unknown family A
HMM of a known family F
PRofile Comparer (PRC, http//supfam.org/PRC)? cal
culates
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Fold recognition results
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Acknowledgements
Julian Gough, University of Bristol Kevin
Karplus, University of California, Santa Cruz