SuperPose: A Web Server for Automated Protein Structure Superposition

1
SuperPose A Web Server for Automated Protein
Structure Superposition

• Gary Van Domselaar
• gvd_at_redpoll.pharmacy.ualberta.ca
• October 08, 2004

2
Introduction

• Who Cares?
• Review of Superposition
• Identifying Corresponding Points Between
  Structures
• Multiple Structure Superposition
• RMSD Calculation
• The SuperPose Web Site

3
Who Cares?

• NMR Spectroscopists

4
Who Cares?

• Structural Biologists

5
Who Cares?

• Evolutionary Biologists

1MYK
6
Principles of Superposition

• How do we superimpose these two cubes?

1MYK
7
Principles of Superposition

• Identify corresponding points.

1MYK
8
Principles of Superposition

• Identify the common center and the principle axes
  for each structure.

1MYK
9
Principles of Superposition

• Translate the two structures so their centers
  overlap.

10
Principles of Superposition

• Rotate the two structures so the average distance
  between corresponding points is minimized,and
  their principal axes overlap.

11
Principles of Superposition

• Rotations can be accomplished by multiplying each
  atom coordinate with an appropriate rotation
  matrix, but this is slow

Counterclockwise about x
Counterclockwise about z
cos? -sin? 0 sin? cos? 0 0 0 1
1 0 0 0 cos? -sin? 0 sin? cos?
Clockwise about x
Clockwise about z
cos? sin? 0 -sin? cos? 0 0 0 1
1 0 0 0 cos? sin? 0 -sin? cos?
12
Principles of Superposition

• A faster way is to use quaternion-based
  superposition to both rotate and minimize the sum
  of residuals
• S.K.Kearsley, On the orthogonal transformation
  used for structural comparisons, Acta Cryst. A45,
  208 (1989)
• http//www-structure.llnl.gov/xray/comp/suptext.ht
  m

13
Identifying Corresponding Points Between Protein
Structures

• Sequence Alignment

PDB_Entry_A 1 SDKIIHLTDDSFDTDVLKA--DGAILVDFWA
EWCGPCKMIAPILDEIADE 48
........... ......... P
DB_Entry_B 1 MVKQIESKTAFQEALDAAGDKLVVVDFSAT
WCGPCKMIKPFFHSLSEK 48 PDB_Entry_A 49
YQGKLTVAKLNIDQNPGTAPKYGIRGIPTLLLFKNGEVAATKVGALSKGQ
98 ....
.............. ..
. PDB_Entry_B 49 YSNVIFL-EVDVDDCQDVASECEVKCTP
TFQFFKKGQ----KVGEFS-GA 92 PDB_Entry_A 99
LKEFLDANLA 108
.... PDB_Entry_B 93 NKEKLEATINELV
105
2TRXA - 3TRXA
14
Identifying Corresponding Points Between Protein
Structures

• Problem Low Homology

3TRX - 3GRX1
Length 163 Identity 11/163 ( 6.7)
Similarity 14/163 ( 8.6) Gaps
139/163 (85.3) Score 16.0
3TRX_
model_de 1
MVKQIESK 8

.... 3GRX_model_1_ 1 ANVEIYTKETCPYSHRAKAL
LSSKGVSFQELPIDGNAAKREEMIKRSGRT
50 3TRX_model_de 9 TAFQ--------------EALDAAG
--DKLVVVDFSATWCGPCKMIKPFF 42
.. .. ..
3GRX_model_1_ 51 TVPQIFIDAQHIGGYDDLYALDAR
GGLDPLLK 82 3TRX_model_de
43 HSLSEKYSNVIFLEVDVDDCQDVASECEVKCTPTFQFFKKGQKV
GEFSGA 92
3GRX_model_1_
83
82 3TRX_model_de 93
NKEKLEATINELV 105
3GRX_model_1_ 83 82
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Identifying Corresponding Points Between Protein
Structures

• Solution Secondary Structural Alignment

3TRX - 3GRX1
Sequence1 3TRX_model_default_chain_default Seque
nce2 3GRX_model_1_chain_default Score.... 600
Test Stat 5.31 Matches.. 64
Sequence1 CEEEECCHHHHHHHHHHHCCEEEEEEEEECCCHHHHH
CCCCCCHHHHHCC Matching.
Sequence2
CEEEEEEECCCHHHHHHHH
HHHHHCC Structure
CBBBBBBBCCCHHHHHHHH HHHHHCC Sequence1
CEEEEEEEECCCHHHHHHHCCCCEEEEEEEECCCCCEEECCCCHHHHHHH
Matching.
Sequence2 CEEEEEECCCCHHHHHHHHHCCCCCC
EEEEECCCCC CHHHHHHHH Structure
CBBBBBBCCCCHHHHHHHHHCCCCCCBBBBBCCCCC
CHHHHHHHH Sequence1 HHHCC Matching.
Sequence2 HHHCCCCCCCC Structure HHHCCCCCCCC
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Identifying Corresponding Points Between Protein
Structures

• Problem Multiple Structural Forms

Length 145 Identity 143/145 (98.6)
Similarity 143/145 (98.6) Gaps
2/145 ( 1.4) Score 730.0
1A29_model_de 1
QLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMI
50
1CLL_model_de
1 LTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQD
MI 49 1A29_model_de 51
NEVDADGNGTIDFPEFLTMMARKMKDTDSEEEIREAFRVFDKDGNGYISA
100
1CLL_model_de
50 NEVDADGNGTIDFPEFLTMMARKMKDTDSEEEIREAFRVFDKDGNGY
ISA 99 1A29_model_de 101
AELRHVMTNLGEKLTDEEVDEMIREADIDGDGQVNYEEFVQMMT
144
1CLL_model_de 100
AELRHVMTNLGEKLTDEEVDEMIREADIDGDGQVNYEEFVQMMTA
144
1A29 - 1CLL
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Identifying Corresponding Points Between Protein
Structures

• Solution Subdomain Alignment

1A29 - 1CLL
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Identifying Corresponding Points Between Protein
Structures

• The Difference Distance Matrix
• Make a Distance Matrix for each structure

2
3
1
1
3
2
4
4
1 2 3 4 1 0 0.9 2.0 1.2 2 0.9 0 3
2.0 0 4 1.2 0
1 2 3 4 1 0 0.9 2.0 2.3 2 0.9 0
3 2.0 0 4 2.3 0
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Identifying Corresponding Points Between Protein
Structures

• The Difference Distance Matrix
• Subtract the dif matrices to make a DD Matrix
• Plot the magnitude of the distance as a color
  shade

1 2 3 4 1 0 0 0 1.1 2 0 0 3
0 0 4 1.1 0
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Identifying Corresponding Points Between Protein
Structures

• Analyze the difference distance matrix for
  similar subdomains.
• The DD Matrix will have regions that are similar,
  and regions that are different.

21
Identifying Corresponding Points Between Protein
Structures
Superposition restricted to residues 5-74
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Identifying Corresponding Points Between Protein
Structures
Superposition restricted to residues 5-74
23
Identifying Corresponding Points Between Protein
Structures
Length 145 Identity 143/145 (98.6)
Similarity 143/145 (98.6) Gaps
2/145 ( 1.4) Score 730.0
1A29_model_de 1
QLTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQDMI
50
1CLL_model_de
1 LTEEQIAEFKEAFSLFDKDGDGTITTKELGTVMRSLGQNPTEAELQD
MI 49 1A29_model_de 51
NEVDADGNGTIDFPEFLTMMARKMKDTDSEEEIREAFRVFDKDGNGYISA
100
1CLL_model_de
50 NEVDADGNGTIDFPEFLTMMARKMKDTDSEEEIREAFRVFDKDGNGY
ISA 99 1A29_model_de 101
AELRHVMTNLGEKLTDEEVDEMIREADIDGDGQVNYEEFVQMMT
144
1CLL_model_de 100
AELRHVMTNLGEKLTDEEVDEMIREADIDGDGQVNYEEFVQMMTA
144
24
Multiple Structure Superposition

• How do you optimally superimpose more than 2
  structures?

25
Multiple Structure Superposition

• Superimpose to an average structure

Average Structure
1
3
2
3-Structure Superposition
Initial 2-Structure Superposition
Structure 3
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Multiple Structure Superposition

• Superposition ordering is important
• Structures should be superposed in order of their
  pairwise structural similarity.
• An 'all-against-all' DD Matrix analysis can be
  used to quickly determine overall relative
  similarity between every pair of structures

Avg RMSD for 3TRX chains A B 1.5 A
Avg RMSD for 3TRX chains A C 1.75 A
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Multiple Structure Superposition

• A structure 'pileup' is created from the DD
  Matrix analysis to determine the superposition
  order.

3TRX_A,D .5A 3TRX_A,B .6A 3TRX_B,D
.7A 3TRX_B,C .8A 3TRX_A,C .9A 3TRX_C,D 1.0
3TRX_A,D .5A 3TRX_A,B .6A 3TRX_B,C .8A
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Multiple Structure Superposition

• Average structures can be sensibly generated only
  from a collection of structures with identical
  sequences
• How do you superimpose a collection of sequences
  with non-identical sequences?
• Progressive pairwise buildup using the pileup as
  a guide.

3TRX_A,D .5A 3TRX_A,B .6A 3TRX_B,C .8A
Superpose Structures A and D 'Anchor' Structure
A, translate/rotate B, add B to A,D 'Anchor'
Structure B, translate/rotate C, Add C to A,B,D
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Multiple Structure Superposition
CLUSTAL W (1.83) multiple sequence
alignment 2TRX_model_default_chain_A
SDKIIHLTDDSFDTDVLKA--DGAILVDFWAEWCGPCKMIAPILDEIADE
2TRX_model_default_chain_B
SDKIIHLTDDSFDTDVLKA--DGAILVDFWAEWCGPCKMIAPILDEIADE
3TRX_model_default_chain_defau
--MVKQIESKTAFQEALDAAGDKLVVVDFSATWCGPCKMIKPFFHSLSEK
..
.. .. 2TRX_model_
default_chain_A YQGKLTVAKLNIDQNPGTAPKYGIR
GIPTLLLFKNGEVAATKVGALSKGQ 2TRX_model_default_chain
_B YQGKLTVAKLNIDQNPGTAPKYGIRGIPTLLLFKNGEV
AATKVGALSKGQ 3TRX_model_default_chain_defau
YSNVIFL-EVDVDDCQDVASECEVKCTPTFQFFKKGQ----KVGEFS-GA
..
...
2TRX_model_default_chain_A
LKEFLDANLA--- 2TRX_model_default_chain_B
LKEFLDANLA--- 3TRX_model_default_chain_defau
NKEKLEATINELV
.
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RMSD Calculation

• The degree of similarity between two or more
  structures is described by its average root mean
  square deviation (RMSD)

x3
x4
x2
y3
y4
y2
x5
y5
x1
x1
y1
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SuperPose

• http//wishart.biology.ualberta.ca/SuperPose/
• Superposition for 2 chains and for multiple
  chains
• Subdomain superposition
• Superposition of structures with low sequence
  identity