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

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

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

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

  2. 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.

  3. 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.

  4. The Distance Matrix and How It’s Read 1 2 3

  5. Assignment of Equivalent Residue Pairs

  6. Additive Similarity Score (general) S = S Sf(i,j) L L • 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. i = 1 j = 1

  7. 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

  8. Elastic Similarity Score | dAij – dBij | q E - • d*ij = the average of dAij and dBij • q E = tolerance of 20% deviation • w(r) = envelope function = exp(-r2/a2) w(d*ij) fE(i,j) = d*ij q E

  9. Robustness of Dali

  10. 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.

  11. 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.

  12. Dendrogram Examination of Relatedness Using a Dendrogram

  13. 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.

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