Databases: Navigating the MSD

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Databases Navigating the MSD
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MSDlite

• A simple form-based query system to search the
  MSD Databases
• Allows multiple search fields to be combined
• Relatively fast, despite performing complex SQL
  queries

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MSDlite

• Strengths
• Weaknesses

• simple, easy to use form
• allows multiple search fields to be combined
• relatively fast, despite performing quite complex
  SQL queries

• not exposing the power of a relational database
• user can't specify the relationship between
  search fields
• "name" AND "title" AND "keyword"
• "name" OR "title" OR "keyword"
• ( "name" OR "title" ) AND NOT "keyword"
• the search form is defined by the authors of the
  search system, not the author of a query

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Complex Searches (Advanced Users)

• Wanted to allow the user to entirely control
  their query developed MSDpro
• Uses an applet to provide a dynamic "form" that
  lets the user
• choose the fields to be searched
• specify relationships between search fields
• choose result fields and how they are presented
• perform "complex" sub-queries e.g. SSM, FASTA
• MSDpro uses an applet for constructing queries
  and a server to execute them
• The user describes their query entirely
  graphically, including logical operations such as
  AND, OR and NOT

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MSD Atlas Pages
You can download coordinates and structure
factors (if available)
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Structural Similarity MSDfold
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If you have to ask.

• Are there any structures in the PDB that are
  similar to mine?
• What SCOP and/or CATH family could my structure
  belong to ?
• Can I get some idea about the possible function
  of my protein based on structural similarity with
  others?
• How do I get a multiple alignment of many of my
  structures ?

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Structure Alignment
Structure alignment may be defined as
identification of residues occupying equivalent
geometrical positions

• Unlike in sequence alignment, residue type is
  neglected
• Used for

• measuring the structural similarity
• protein classification and functional analysis
• database searches

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Methods

• Many methods are known

• Distance matrix alignment (DALI, Holm Sander,
  EBI)
• Vector alignment (VAST, Bryant et. al. NCBI)
• Depth-first recursive search on SSEs (DEJAVU,
  Madsen Kleywegt, Uppsala)
• Combinatorial extension (CE, Shindyalov Bourne,
  SDSC)
• Dynamical programming on Ca (Gerstein Levitt)
• Dynamical programming on SSEs (SSA, Singh
  Brutlag, Stanford University)
• many others

• MSDfold (SSM) employs a 2-step procedure

• Initial structure alignment and superposition
  using SSE graph matching
• Ca - alignment

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Graph representation of SSEs
E. M. Mitchell et al. (1990) J. Mol. Biol. 212151
SSE graphs differ from conventional chemical
graphs only in that they are labelled by vectors
of properties. In graph matching, the labels are
compared with tolerances chosen empirically.
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SSE graph matching
A
Matching the SSE graphs yields a correspondence
between secondary structure elements, that is,
groups of residues. The correspondence may be
used as initial guess for structure superposition
and alignment of individual residues.
B
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Ca - alignment

• SSE-alignment is used as an initial guess for
  Ca-alignment
• Ca-alignment is an iterative procedure based on
  the expansion of shortest contacts at best
  superposition of structures

• Ca-alignment is a compromise between the
  alignment length Nalign and r.m.s.d. Longest
  contacts are unmapped in order to maximise the
  Q-score

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Using MSDfold
Discover hitherto unknown relationships
88 structural identity
11 Sequence identity
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MSDfold Search Interface
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MSDfold Output

• Table of matched Secondary Structure Elements
• Table of matched backbone Ca-atoms with distances
  between them at best structure superposition
• Rotation-translation matrix of best structure
  superposition
• Visualisation in Jmol and Rasmol
• r.m.s.d. of Ca-alignment
• Length of Ca-alignment Nalign
• Number of gaps in Ca-alignment
• Quality score Q
• Statistical significance scores P(S), Z
• Sequence identity

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Results Page For Pairwise Alignment
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Specific Pairwise Results
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Structural Alignment
Residue by residue structural alignment result
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Multiple 3D Alignment

• More than 2 structures are aligned simultaneously
• Multiple alignment is not equal to the set of
  all-to-all pairwise alignments
• Helps to identify common structure motifs for a
  whole family of structures

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Multiple 3D Alignment Interface
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Results From Multiple 3D Alignment
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Conclusions from use of MSDfold

• residue identity may play a much less significant
  role in protein structure than often believed
• as a consequence, the role of residue identity in
  protein function may be often overestimated
• using sequence identity for the assessment of
  structural or functional features may give more
  false negatives than expected
• physical-chemical properties of residues should
  be given preference over residue identity in
  structure and function analysis
• modern methods for structure alignment are
  efficient there is little sense to use sequence
  alignment in structure-related studies