Dali: A Protein Structural Comparison Algorithm Using 2D Distance Matrices

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Dali A Protein Structural Comparison Algorithm
Using 2D Distance Matrices
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Main Points for Discussion

• Overview of why structural comparison can be a
  useful mode of analysis.
• Using a 2-D distance matrix to represent a 3-D
  protein structure.
• Specific computer algorithms that have been used
  to accomplish this analysis, including Monte
  Carlo optimization.
• Further applications of Dali.

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Why consider structural comparison?

• 1D sequence comparisons has traditionally been
  (and still is) used to determine degree of
  relatedness, although a low degree of sequence
  homology may yield surprisingly similar
  structures.
• 3D structural alignment is aimed at providing
  more information about the structure-function
  similarities between proteins with
  non-detectable evolutionary relationships.

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The Distance Matrix and How Its Read
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2
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Assignment of Equivalent Residue Pairs
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Additive Similarity Score (general)
S S S f(i,j)
L
L
i 1
j 1

• i and j are labeled pairs of equivalent (matched)
  residues (i.e. i iA,iB).
• f similarity measure based on Ca-Ca distances
  dAij and dBij
• Largest S corresponds to optimal set of
  equivalencies.

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Rigid Similarity Score
fR(i,j) q R dAij dBij

• dAij and dBij are equivalenced residues
• in proteins A and B.
• q R zero level of similarity

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Elastic Similarity Score
dAij dBij
q E -
w(dij)
fE(i,j)
dij
q E

• dij the average of dAij and dBij
• q E tolerance of 20 deviation
• w(r) envelope function exp(-r2/a2)

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Robustness of Dali
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Quality of Generated Alignments

• Accuracy was verified by examining conserved
  functional residues in seeemingly divergent
  structures.
• The elasticity score is useful in that it
  captures relative movements of structural
  elements (e.g. ATP binding site in hsp70) and
  leaves only extremely non-homologous loops
  unaligned.

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Quality of Generated Alignments (cont.)

• Detection of inter-domain motion brings
  functionally important residues into focus (e.g.
  ATP binding site in hsp70).
• Manipulation of the elastic similarity score
  determines the stringency of the alignment.

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Dendrogram
Examination of Relatedness Using a Dendrogram
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Further Applications of Dali

• Continuing further in an attempt to map the
  entire protein space using quantitative
  comparisons between structures (correspondence
  analysis on p. 133)
• Applications to residue-residue energy
  interactions to create a more accurate
  biochemical representation of the protein. Also
  able to yield more useful information to predict
  3D structure from amino acid sequence due to the
  energies of interacting residues.