Automated Methods for Structure Comparison

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Automated Methods for Structure Comparison

• Basic problem how are any two given structures
  to be automatically compared in a meaningful way?
• How are distant relationships to be recognized?
• program method
• DALI distance matrix comparison (basis
• for FSSP structural classification)
• SSAP dynamic programming (used in CATH
• to classify topologies)
• VAST convert secondary structures to vectors
• and align vectors

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Structure comparison is pretty easy when two
proteins are very similar

• when two proteins are so similar that the
  sequences can be reliably aligned, say gt35
  identical, structure comparison can proceed from
  the seq. alignment
• 1. Align the sequences
• sequence 1 YIREV-GKL
• sequence 2 YITQVRNKA
• 2. Superpose the structures to minimize the RMSD
  for equivalent residue pairs in the alignment

note these structures do not correspond to the
sequences above
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it is harder when the proteins are very
different...

• if one cannot align the sequence reliably, how
  does one establish which residues, if any, play
  equivalent structural roles in the two proteins?
• the answer is to attempt to align the structures
  directly in such a way that structural
  equivalencies in the two proteins are revealed
• we will discuss how the distance-matrix based
  algorithm of DALI solves this problem

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Distance Matrices

• 2D representation of 3D structure
• plot sequence against itself
• identify pairs of residues which are close in
  space to each other
• usually distance between C-alpha carbons is used
• identify closeness between residues as dark parts
  of the matrix

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Distance matrices
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Different substructures, such as secondary or
supersecondary structures, give rise to distinct
patterns in the matrix
e.g. antiparallel vs. parallel beta-sheets
in principle, one could recognize structural
similarity in two proteins by comparing
patterns in distance matrices, but its not that
simple
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Problem two structures with the same topology
may differ in the precise location of secondary
structure elements along the sequence, i.e. loop
lengths may differ
same fold, different matrices
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Or two common architectures may differ in
connectivity (topology)...
both three-stranded antiparallel beta-sheets
how might we compare their distance matrices to
reveal this similarity?
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DALI algorithm

• not useful to compare entire matrices
• instead, chop distance matrices into all possible
  submatrices of 6x6 amino acids
• compare this set of submatrices for pattern
  similarities rather than comparing entire matrix

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1. identify a pair of matching submatrices within
the two matrices
make an initial sequence alignment from this
match...
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2. Identify a second pair which overlaps the
first(contains one common structural element)
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3. Combine overlapping pairs
overall alignment of structurally equivalent
sequence regions
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4. Rearrange and collapse the matrixaccording
to the aligned regions of the sequence
now the common structural elements are aligned as
are the structurally equivalent residues in the
sequence!
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All together now...
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The Power of DALI

• DALI is quite powerful because it can recognize
  architectural similarities even when topologies
  are different.
• It is also flexible because it can be made more
  topologically restrictive (i.e. no swapping of
  segments in chain allowed) to focus on closer
  relationships