Matching Problems in Bioinformatics

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Matching Problems in Bioinformatics

• Charles Yan
• Fall 2008

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Matching Problem

• Given a string P (pattern) and a long string T
  (text), find all occurrences, if any, of P in T.
• Example
• T Given a string P (pattern) and a long string T
  (text), find all occurrences, if any, of P in T.
• P any
• Exact matching Does not allow any mismatch
• Inexact matching Allow up to k mismatches

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Matching Problem

• Unix grep
• MS word find
• Genbank http//www.ncbi.nlm.nih.gov/Genbank/
• Human genome
• http//www.ncbi.nlm.nih.gov/projects/mapview/map_s
  earch.cgi?taxid9606
• Given TTGTTCCGGTTAAAGATGGTGAAAATTTTT, does it
  appear in human genome? Where?
• How about ACCCCCAGGCGAGCATCTGACAGCCTGGAGCAGCACACA
  CAACCCCAGGCGAG?

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Motifs

• A motif is a conserved element corresponding to a
  certain function (or structure). Occurrence of a
  motif in a protein is likely to indicate that the
  protein has the corresponding function.
• Motifs are usually represented using alignment or
  regular expression

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Motifs
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Motifs

• Protein function prediction using motifs
• Each protein function is characterized by one
  single motif or multiple motifs .
• If a protein contain the motif(s), it probably
  has the function that the motif(s) corresponds
  to.
• A pertinent analogy is the use of fingerprints by
  the police for identification purposes. A
  fingerprint is generally sufficient to identify a
  given individual. Similarly, motif(s) can be used
  to formulate hypotheses about the function of a
  newly discovered protein.

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PROSITE

• PROSITE (http//ca.expasy.org/prosite/) is a
  database of protein families and domains.
  (Starting in 1988).
• PROSITE currently contains patterns (motifs) and
  profiles specific for more than a thousand
  protein families or domains. Release 20.36, of
  22-Jul-2006 (contains 1528 documentation
  entries).
• Each of these signatures comes with documentation
  providing background information on the structure
  and function of these proteins.

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PROSITE
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PROSITE
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PROSITE
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PROSITE
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PROSITE

• Steps in the development of a new motif
• Select a set of sequences that belong to a
  function family. Make a multiple alignment.
• Find a short (not more than four or five residues
  long) conserved sequence (core motif) which is
  part of a region known to be important or which
  include biologically significant residue(s).

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PROSITE

• Steps in the development of a new motif (cont.)
• The most recent version of the Swiss-Prot
  knowledgebase is then scanned with these core
  pattern(s). If a core motif will detect all the
  proteins in the family and none (or very few) of
  the other proteins, we can stop at this stage.
• In most cases we are not so lucky and we pick up
  a lot of extra sequences which clearly do not
  belong to the group of proteins under
  consideration. A further series of scans,
  involving a gradual increase in the size of the
  motif, is then necessary. In some cases we never
  manage to find a good motif.

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PROSITE

• The motif are described using the following
  conventions
• The standard IUPAC one-letter codes for the amino
  acids are used.
• The symbol 'x' is used for a position where any
  amino acid is accepted.
• Ambiguities are indicated by listing the
  acceptable amino acids for a given position,
  between square parentheses ' '. For example
  ALT stands for Ala or Leu or Thr.
• Ambiguities are also indicated by listing between
  a pair of curly brackets ' ' the amino acids
  that are not accepted at a given position. For
  example AM stands for any amino acid except
  Ala and Met.
• Each element in a pattern is separated from its
  neighbor by a '-'.

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PROSITE

• The motif are described using the following
  conventions (Cont.)
• Repetition of an element of the pattern can be
  indicated by following that element with a
  numerical value or a numerical range between
  parenthesis. Examples x(3) corresponds to x-x-x,
  x(2,4) corresponds to x-x or x-x-x or x-x-x-x.
• When a pattern is restricted to either the N- or
  C-terminal of a sequence, that pattern either
  starts with a 'lt' symbol or respectively ends
  with a 'gt' symbol. In some rare cases (e.g.
  PS00267 or PS00539), 'gt' can also occur inside
  square brackets for the C-terminal element.
  'F-GSTV-P-R-L-Ggt' means that either
  'F-GSTV-P-R-L-G' or 'F-GSTV-P-R-Lgt' are
  considered.
• A period ends the pattern.
• Examples
• AC-x-V-x(4)-ED.This pattern is translated
  as Ala or Cys-any-Val-any-any-any-any-any but
  Glu or Asp

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PROSITE
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PROSITE
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PROSITE

• A profile or weight matrix is a table of
  position-specific amino acid weights and gap
  costs. These numbers (also referred to as scores)
  are used to calculate a similarity score for any
  alignment between a profile and a sequence, or
  parts of a profile and a sequence. An alignment
  with a similarity score higher than or equal to a
  given cut-off value constitutes a motif
  occurrence.

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PROSITE
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Motifs and Matching

• Motif Finding
• Given a set of protein sequences, to find the
  motif(s) that are shared by these proteins.
• Motif Scanning
• Given a motif and a protein sequence, to find
  the occurrences (not necessary identical) of the
  motif on the protein sequences.
• --The Matching Problem!

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From Single Motif to Multiple Motifs

• One single motif is not sufficient to predict a
  protein function. Multiple motifs have stronger
  predicting power.

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Multiple Motifs

• Protein function prediction using multiple motifs
• Each protein function is characterized by a set
  of motifs (in stead of a single one).
• If a protein contain a set of motifs, it probably
  has the function that the set of motifs
  correspond to.

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PRINTS

• PRINTS (http//umber.sbs.man.ac.uk/dbbrowser/PRINT
  S/ ) is a database of protein fingerprints.
• A fingerprint is a group of conserved motifs used
  to characterize a protein family
• ftp.bioinf.man.ac.uk/pub/prints
• PRINTS is now maintained at the University of
  Manchester
• PRINTS VERSION 38.1 (25 May, 2007)
• 1904 FINGERPRINTS, encoding 11,451 single motifs

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PRINTS

• Two types of fingerprint are represented in the
  database, i.e. they are either simple or
  composite, depending on their complexity simple
  fingerprints are essentially single-motifs while
  composite fingerprints encode multiple motifs.
  The bulk of the database entries are of the
  latter type because discrimination power is
  greater for multi-component searches.
• Usually the motifs do not overlap, but are
  separated along a sequence, though they may be
  contiguous in 3D-space.
• Fingerprints can encode protein folds and
  functionalities more flexibly and powerfully than
  can single motifs, full diagnostic potency
  deriving from the mutual context provided by
  motif neighbors.

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PRINTS
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PRINTS
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PRINTS

• a) General field

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PRINTS

• FPScan
• Submitting a PROTEIN sequence find the closest
  matching PRINTS fingerprint/s.

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PRINTS
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PRINTS
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PRINTS
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PRINTS
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Related Projects

• InterPro - Integrated Resources of Proteins
  Domains and Functional Sites
• BLOCKS - BLOCKS db
• Pfam - Protein families db (HMM derived) Mirror
  at St. Louis (USA)
• PRINTS - Protein Motif fingerprint db
• ProDom - Protein domain db (Automatically
  generated)
• PROTOMAP - An automatic hierarchical
  classification of Swiss-Prot proteins
• SBASE - SBASE domain db
• SMART - Simple Modular Architecture Research Tool
  
• TIGRFAMs - TIGR protein families db

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Motifs and Matching

• Motif Finding
• Given a set of protein sequences, to find the
  motif(s) that are shared by these proteins.
• Motif Scanning
• Given a motif and a protein sequence, to find
  the occurrences (not necessary identical) of the
  motif on the protein sequences.
• --The Matching Problem!