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MSDfold (SSM) S econdary S tructure M atching

MSDfold (SSM) S econdary S tructure M atching A web service for protein structure comparison and structure searches Eugene Krissinel. http://www.ebi.ac.uk/msd-srv/ssm/ssmstart.html. Structure alignment.

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MSDfold (SSM) S econdary S tructure M atching

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  1. MSDfold (SSM) Secondary Structure Matching A web service for protein structure comparison and structure searches Eugene Krissinel http://www.ebi.ac.uk/msd-srv/ssm/ssmstart.html

  2. 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

  3. 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 other • SSM employs a 2-step procedure: • Initial structure alignment and superposition using SSE graph matching • Ca - alignment

  4. r2 a2 r1 a1 t L Graph representation of SSEs E. M. Mitchell et al. (1990) J. Mol. Biol. 212:151 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.

  5. H1 A B H1 H2 S1 S1 S4 S2 H2 H1 S3 S2 S1 S3 H4 S2 S4 H1 H5 S5 S2 S3 S6 S1 S4 S7 H2 H3 S7 H2 H3 H6 S6 H4 S3 H5 S4 S5 H6 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

  6. chain A matched helices matched strands chain B 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 Nalignand r.m.s.d. Longest contacts are unmapped in order to maximise the Q-score:

  7. Multiple structure 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

  8. Iterative removal of non-aligning SSEs best pairwise alignments may be multiply aligned from pairwise relations Helices Strands do not multiply align, but one still can try to align them by probing alternative (not best) alignments C A B

  9. Iterative removal of non-aligning SSEs 4 alternative pairwise alignments make up to 4 multiple alignments: 1 A1 - B1 - C1 A1 - B2 - C1 A2 - B1 - C1 A2 - B2 - C1 1 1 2 C prohibitive for Complexity 2 A structures B

  10. Start Calculate all-to-all pairwise alignments Are there non-aligning SSEs? Remove one non-aligning SSE with lowest score Quit Iterative removal of non-aligning SSEs Heuristics: remove non-aligning SSE with lowest alignment score and reiterate all alignment 1 1 1 2 C 2 Yes No A B

  11. Multiple SSE alignment Initial C alignment Choose structure, closest to X, as central star  and align all the rest to  Superpose structures and calculate consensus structure X Score improved? Quit Multiple C refinement Central star & consensus  Yes No Unmap groups of atoms with highest distance score D in order to maximise the score C B A X

  12. Pairwise Alignment vs. Multiple Alignment Addition of 1MGW:A (close neighbour to 1SAR:A) spots out a common motif of -sheet and -helix Best pairwise alignment of 1SAR:A and 1D1F:B includes only -sheet

  13. SSM server map http://www.ebi.ac.uk/msd-srv/ssm

  14. SSM 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

  15. Scoring at low structural similarity - 1KNO:A vs SCOP 1.61 Maximal Q-score d1di2a_ (69 res) Q-score 0.213 RMSD 2.43 Nalign 67/184 P 0.55 Lowest RMSD d1emn_1 (43 res) Q-score 0.019 RMSD 0.9 Nalign13/184 P 0.075 Highest Nalign d1elxb_ (449 res) Q-score 0.02 RMSD 5.82 Nalign89/184 P ~1

  16. Performance data 4 50 s 1

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