MCSG 2001 structures

protein structure and function

Classification: understanding the diversity and principles of

Tool: structure comparison

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

Structure Comparison

• Evolutionary relationship• Structure classification

Growth factorCytokine

Shapiro & Harris, 2000

9% sequence identity

Gerstein

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.)

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)

Gerstein

Gerstein

Gerstein

SAP (iterated DDP)

DDP

Dali

Dali’s idea

3D Lookup

Holm & Sander (1995)

3D Lookup

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/)

Complication: alternative alignments

Results of different methods on the comparison of Azurin (1azc:A) vs plastocyanin (1plc)

Complication: permutation

N

C

AB

DC N

C

AB

DC

..A..B..C..D.. ..C..D..A..B..

Circular Permutation (CP)

1nls (Concanavalin) 1led (Lectin)

N

C

N C

A real example of CP

Angle-distance map:

SSE matching:

FLASH’s algorithm

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:

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)

Unique Capabilities:

• alternative alignments allowing sub-domain motif (structural building block) discovery

• permutation detection at all levels of complexity