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 2 1 3

5. Assignment of Equivalent Residue Pairs

6. Additive Similarity Score (general) i and j are labeled pairs of equivalent (matched) residues (i.e. i = i A,i B ).   = similarity measure based on Ca-Ca distances dAij and dBij Largest S corresponds to optimal set of equivalencies. S =   (i,j) i = 1j = 1 LL

7. Rigid Similarity Score  R (i,j) =  R – | d A ij – d B ij | d A ij and d B ij are equivalenced residues in proteins A and B.   R = zero level of similarity

8. Elastic Similarity Score d * ij = the average of d A ij and d B ij   E = tolerance of 20% deviation w(r) = envelope function = exp(-r 2 /  2 )   (i,j) = | d A ij – d B ij |  E d * ij w(d * ij )  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. Examination of Relatedness Using a Dendrogram 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.