mcsg 2001 structures protein structure and function classification: understanding the diversity and...
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MCSG 2001 structures
protein structure and function
Classification: understanding the diversity and principles of
Tool: structure comparison
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Why compare protein structures?
Learn about– structure-function relationships– evolution– common building blocks – motifs
Make order out of the universe of protein structures
Help structure predictionInge Jonassen
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Structure Comparison
• Evolutionary relationship• Structure classification
Growth factorCytokine
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Shapiro & Harris, 2000
9% sequence identity
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Gerstein
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Strategies
Bottom Upfind local matches first, then solve the combinatorial problem to identify the largest cluster of matching substructures (e.g., Dali, CE, etc.)
Top Downfind a rough global alignment first, then use a refinement procedure to identify details of local matches (e.g., 3D look-up, subgraph isomorphism, etc.)
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Types of substructure used
Atom/atom group Residue Fragment Secondary structure element (SSE) Structure described by elements of the
chosen type (e.g. molecular surface)
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Gerstein
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Gerstein
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Gerstein
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SAP (iterated DDP)
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DDP
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Dali
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Dali’s idea
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3D Lookup
Holm & Sander (1995)
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3D Lookup
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Structure Comparison Tools
DALI ( http://www2.ebi.ac.uk/dali/ ) CE ( http://cl.sdsc.edu/ ) VAST (
http://www.ncbi.nlm.nih.gov/Structure/VAST/vast.html )
Prosup ( http://www.came.sbg.ac.at ) FLASH (http://thr.ibms.sinica.edu.tw/flash/)
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Complication: alternative alignments
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Results of different methods on the comparison of Azurin (1azc:A) vs plastocyanin (1plc)
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Complication: permutation
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N
C
AB
DC N
C
AB
DC
..A..B..C..D.. ..C..D..A..B..
Circular Permutation (CP)
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1nls (Concanavalin) 1led (Lectin)
N
C
N C
A real example of CP
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Angle-distance map:
SSE matching:
FLASH’s algorithm
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Greedy selection of distinct alignment solutions
g - f’ 50.4
d - c’ 42.1
f - e’ 33.7
e - d’ 33.3
b - a’ 30.4
c - b’ 27.2
c - e’ 8.9
e - a’ 7.7
f - b’ 6.3
b - d’ 5.8
g - c’ 4.6
d - f’ 3.8
f - a’ 1.5
c - a’ 1.2
a - c’ 1.2
(1) g - f’ d - c’ f - e’ e - d’ b - a’ c - b’
(2) c - e’ b - d’ d - f’
(3) e - a’ f - b’ g - c’
Optimal: Alternative:
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Scrambled Protein Pair
A B C D
A D C B
N
N’
C
C’
N
C
N’
C’
“…few, if any, are able to detect permutations directly.”- Robert B. Russell (2002)
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Unique Capabilities:
• alternative alignments allowing sub-domain motif (structural building block) discovery
• permutation detection at all levels of complexity