1. Structural Biology and Molecular Biophysics
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Sequence co-evolution gives 3D contacts and structures of protein complexes

  1. Thomas A Hopf
  2. Charlotta P I Schärfe
  3. João P G L M Rodrigues
  4. Anna G Green
  5. Oliver Kohlbacher
  6. Chris Sander  Is a corresponding author
  7. Alexandre M J J Bonvin  Is a corresponding author
  8. Debora S Marks  Is a corresponding author
  1. Harvard University, United States
  2. Technische Universität München, Germany
  3. University of Tübingen, Germany
  4. Bijvoet Center for Biomolecular Research, Utrecht University, Netherlands
  5. Memorial Sloan Kettering Cancer Center, United States
Research Article
Cite this article as: eLife 2014;3:e03430 doi: 10.7554/eLife.03430
7 figures, 1 table, 270 data sets and 7 additional files

Figures

Figure 1 with 1 supplement
Co-evolution of residues across protein complexes from the evolutionary sequence record.

(A) Evolutionary pressure to maintain protein–protein interactions leads to the co-evolution of residues between interacting proteins in a complex. By analyzing patterns of amino acid co-variation in an alignment of putatively interacting homologous proteins (left), evolutionary couplings between co-evolving inter-protein residue pairs can be identified (middle). By defining distance restraints on these pairs, the 3D structure of the protein complex can be inferred using docking software (right). (B) Distribution of E. coli protein complexes of known and unknown 3D structure where both subunits are close on the bacterial genome (left), allowing sequence pair matching by genomic distance. For a subset of these complexes, sufficient sequence information is available for evolutionary couplings analysis (dark blue bars). As more genomic information is created through on-going sequencing efforts, larger fractions of the E. coli interactome become accessible for EVcomplex (right). A detailed version of the workflow used to calculate all E. coli complexes currently for which there is currently enough sequence information is shown in Figure1—figure supplement 1.

https://doi.org/10.7554/eLife.03430.003
Figure 1—figure supplement 1
Details of the EVcomplex Pipeline.
https://doi.org/10.7554/eLife.03430.004
Figure 2 with 8 supplements
Evolutionary couplings capture interacting residues in protein complexes.

(A) Inter- and Intra-EC pairs with high coupling scores largely correspond to proximal pairs in 3D, but only if they lie above the background level of the coupling score distribution. To estimate this background noise a symmetric range around 0 is considered with the width being defined by the minimum inter-EC score. For the protein complexes in the evaluation set, this distribution is compared to the distance in the known 3D structure of the complex that is shown here for the methionine transporter complex, MetNI. (Plots for all complexes in the evaluation set are shown in Figure 2—figure supplement 1 and 2.) (B) A larger distance from the background noise (ratio of EC score over background noise line) gives more accurate contacts. Additionally, the higher the number of sequences in the alignment the more reliable the inferred coupling pairs are which then reduces the required distance from noise (different shades of blue). Residue pairs with an 8 Å minimum atom distance between the residues are defined as true positive contacts, and precision = TP/(TP + FP). The plot is limited to range (0,3) which excludes the histidine kinase—response regulator complex (HK–RR)—a single outlier with extremely high number of sequences. (C) To allow the comparison across protein complexes and to estimate the average inter-EC precision for a given score threshold independent of sequence numbers, the raw couplings score is normalized for the number of sequences in the alignment, resulting in the EVcomplex score. In this work, inter-ECs with an EVcomplex score ≥0.8 are used. Note: the shown plot is cut off at a score of 2 in order to zoom in on the phase change region and the high sequence coverage outlier HK-RR is excluded. (D) For complexes in the benchmark set, inter-EC pairs with EVcomplex score ≥0.8 give predictions of interacting residue pairs between the complex subunits to varying accuracy (8 Å TP distance cutoff). All predicted interacting residues for complexes in the benchmark set that had at least one inter-EC above 0.8 are shown as contact maps in Figure 2—figure supplement 3–8.

https://doi.org/10.7554/eLife.03430.005
Figure 2—figure supplement 1
Distribution and accuracy of raw EC scores for all complexes in evaluation set.
https://doi.org/10.7554/eLife.03430.006
Figure 2—figure supplement 2
Distribution and accuracy of raw EC scores for all complexes in evaluation set (2).
https://doi.org/10.7554/eLife.03430.007
Figure 2—figure supplement 3
Contact maps of all complexes with solved 3D structure with inter-ECs above EVcomplex score of 0.8.

Predicted coevolving residue pairs with an EVcomplex score ≥0.8 and all inter-ECs up to the rank of the last include inter-EC are visualized in complex contact maps (red dots: inter-ECs, green and blue dots: intra-ECs for monomer 1 and 2, respectively). Top left and bottom right quadrants: intra-ECs; top right and bottom left quadrants: inter-ECs. Inter- and intra-protein crystal structure contacts at minimum atom distance cutoffs of 5/8/12 Å are shown as dark/middle/light gray dots, respectively; missing data in the crystal structure as shaded blue rectangles.

https://doi.org/10.7554/eLife.03430.008
Figure 2—figure supplement 4
Contact maps of all complexes with solved 3D structure with inter-ECs above EVcomplex score of 0.8 (2).
https://doi.org/10.7554/eLife.03430.009
Figure 2—figure supplement 5
Contact maps of all complexes with solved 3D structure with inter-ECs above EVcomplex score of 0.8 (3).
https://doi.org/10.7554/eLife.03430.010
Figure 2—figure supplement 6
Contact maps of all complexes with solved 3D structure with inter-ECs above EVcomplex score of 0.8 (4).
https://doi.org/10.7554/eLife.03430.011
Figure 2—figure supplement 7
Contact maps of all complexes with solved 3D structure with inter-ECs above EVcomplex score of 0.8 (5).
https://doi.org/10.7554/eLife.03430.012
Figure 2—figure supplement 8
Contact maps of all complexes with solved 3D structure with inter-ECs above EVcomplex score of 0.8 (6).
https://doi.org/10.7554/eLife.03430.013
Figure 3 with 1 supplement
Blinded prediction of evolutionary couplings between complex subunits with known 3D structure.

Inter-ECs with EVcomplex score ≥0.8 on a selection of benchmark complexes (monomer subunits in green and blue, inter-ECs in red, pairs closer than 8 Å by solid red lines, dashed otherwise). The predicted inter-ECs for these ten complexes were then used to create full 3D models of the complex using protein–protein docking. For the fifteen complexes for which 3D structures were predicted using docking, energy funnels are shown in Figure 3—figure supplement 1.

https://doi.org/10.7554/eLife.03430.015
Figure 3—figure supplement 1
Comparison of Interface RMSD to HADDOCK score.

The HADDOCK scores of docked models are plotted against their iRMSDs to the bound complex crystal. Gray data points correspond to models created without any ECs as unambiguous restraints whereas blue dots correspond to model created using all inter-couplings with EVcomplex score ≥0.8. HADDOCK score outliers with scores >100 are not shown, and any model with an iRMSD >35 Å is displayed as iRMSD = 35 Å for visualization purposes.

https://doi.org/10.7554/eLife.03430.016
Evolutionary couplings give accurate 3D structures of complexes.

EVcomplex predictions and comparison to crystal structure for (A) the methionine-importing transmembrane transporter heterocomplex MetNI from E. coli (PDB: 3tui) and (B) the gamma/epsilon subunit interaction of E. coli ATP synthase (PDB: 1fs0). Left panels: complex contact map comparing predicted inter-ECs with EVcomplex score ≥0.8 (red dots, upper right quadrant) and intra-ECs (up to the last chosen inter-EC rank; green and blue dots, top left and lower right triangles) to close pairs in the complex crystal (dark/mid/light gray points for minimum atom distance cutoffs of 5/8/12 Å for inter-subunit contacts and dark/mid gray for 5/8 Å within the subunits). Inter-ECs with an EVcomplex score ≥0.8 are also displayed on the spatially separated subunits of the complex (red lines on green and blue cartoons, couplings closer than 8 Å in solid red lines, dashed otherwise, lower left). Right panels: superimposition of the top ranked model from 3D docking (green/blue cartoon, left) onto the complex crystal structure (gray cartoon) and close-up of the interface region with highly coupled residues (green/blue spheres).

https://doi.org/10.7554/eLife.03430.017
Figure 5 with 3 supplements
Evolutionary couplings in complexes of unknown 3D structure.

Inter-ECs for five de novo prediction candidates without E. coli or interaction homolog complex 3D structure (Subunits: blue/green cartoons; inter-ECs with EVcomplex score ≥0.8: red lines). For complex subunits which homomultimerize (light/dark green cartoon), inter-ECs are placed arbitrarily on either of the monomers to enable the identification of multiple interaction sites. Contact maps for all complexes with unsolved structures are provided in Figure 5—figure supplement 1 and 2. Left to right: (1) the membrane subunit of methionine-importing transporter heterocomplex MetI (PDB: 3tui) together with its periplasmic binding protein MetQ (Swissmodel: P28635); (2) the large and small subunits of acetolactate synthase IlvB (Swissmodel: P08142) and IlvN (PDB: 2lvw); (3) panthotenate synthase PanC (PDB: 1iho) together with ketopantoate hydroxymethyltransferase PanB (PDB: 1m3v); (4) subunits a and b of ATP synthase (model for a subunit a predict with EVfold-membrane, PDB: 1b9u for b subunit), for detailed information see Figure 6; and (5) the complex of UmuC (model created with EVfold) with one possible conformation of UmuD (PDB: 1i4v) involved in DNA repair and SOS mutagenesis. For alternative UmuD conformation, see Figure 5—figure supplement 3.

https://doi.org/10.7554/eLife.03430.018
Figure 5—figure supplement 1
Contact maps of all complexes without solved 3D structure with at least one inter-ECs above EVcomplex score of 0.8.

Inter-ECs are shown as red dots in the top right and bottom left quadrant while intra-ECs of the two monomers are shown in green and blue in the top left and bottom right quadrant, respectively.

https://doi.org/10.7554/eLife.03430.019
Figure 5—figure supplement 2
Contact maps of all complexes without solved 3D structure with at least one inter-ECs above EVcomplex score of 0.8 (2).
https://doi.org/10.7554/eLife.03430.020
Figure 5—figure supplement 3
Details of the predicted UmuCD interaction residues.
https://doi.org/10.7554/eLife.03430.021
Figure 6 with 1 supplement
Predicted interactions between the a-, b-, and c-subunits of ATP synthase.

(A) The a- and b- subunits of E. coli ATP synthase are known to interact, but the monomer structure of subunits a and b and the structure of their interaction in the complex are unknown. (B) EVcomplex prediction (right matrix) for ATP synthase subunit interactions compared to experimental evidence (left matrix), which is either strong (left, solid blue squares) or indicative (left, crosshatched squares). Interactions that have experimental evidence, but are not predicted at the 0.8 threshold are indicated as yellow dots. (C) Left panel: residue detail of predicted residue–residue interactions (dotted lines) between subunit a and b (residue numbers at the boundaries of transmembrane helices in gray). Right panel: proposed helix–helix interactions between ATP synthase subunits a (green), b (blue, homodimer), and the c ring (gray). The proposed structural arrangement is based on analysis of the full map of inter-subunit ECs with EVcomplex score ≥0.8 (Figure 6—figure supplement 1).

https://doi.org/10.7554/eLife.03430.022
Figure 6—figure supplement 1
Contact map of predicted ECs in the ATPsynthase a and b subunits.

Inter-ECs are shown as red dots in the top right and bottom left quadrant while intra-ECs of the two monomers are shown in green and blue in the top left and bottom right quadrant, respectively.

https://doi.org/10.7554/eLife.03430.023
Author response image 1

Tables

Table 1

EVcomplex predictions and docking results for 15 protein complexes

https://doi.org/10.7554/eLife.03430.014
EVcomplex contactsDocking quality (iRMSD)
Complex nameSubunitsSeqsECsTP rate§Top ranked model#Best model
Carbamoyl-phosphate synthaseCarB:CarA2.3170.881.91.9
Aminomethyltransferase/Glycine cleavage system H proteinGcsH:GcsT2.950.25.45.4
Histidine kinase/response regulatorKdpD:CheY (T. maritima)95.4780.722.12.0
Ubiquinol oxidaseCyoB:CyoA1.0110.551.81.2
Outer membrane usher protein/Chaperone proteinFimD:FimC3.660.833.23.0
Molybdopterin synthaseMoaD:MoaE3.681.04.44.1
Methionine transporter complexMetN:MetI1.9140.861.51.2
Dihydroxyacetone kinaseDhaL:DhaK1.4120.426.72.4
Vitamin B12 uptake systemBtuC:BtuF3.250.62.82.8
Vitamin B12 uptake systemBtuC:BtuD9.8210.881.10.9
ATP synthase γ and ε subunitsAtpE:AtpG2.9150.531.41.4
IIA-IIB complex of the N,N'-diacetylchitobiose (Chb) transporterPtqA:PtqB3.150.27.25.5
30 S Ribosomal proteinsRS3:RS141.4110.911.11.1
Succinatequinone oxido-reductase flavoprotein/iron-sulfur subunitsSdhB:SdhA3.080.621.41.4
30 S Ribosomal proteinsRS10:RS141.261.05.32.5
  1. Number of non-redundant sequences in concatenated alignment normalized by alignment length.

  2. Inter-ECs with EVcomplex score ≥0.8.

  3. §

    True Positive rate for inter-ECs above score threshold.

  4. #

    iRMSD positional deviation of model from known structure, for docked model with best HADDOCK score.

  5. Lowest iRMSD observed across all models.

Data availability

The following data sets were generated
  1. 1
The following previously published data sets were used
  1. 1
  2. 2
  3. 3
    Crystal Structure of an E.coli Chemotaxis Protein, Chez
    1. Zhao R
    2. Collins EJ
    3. Bourret RB
    4. Silversmith RE
    (2001)
    ID 1KMI. Publicly available at the RCSB Protein Data Bank.
  4. 4
  5. 5
  6. 6
  7. 7
  8. 8
  9. 9
  10. 10
  11. 11
  12. 12
  13. 13
  14. 14
  15. 15
  16. 16
  17. 17
  18. 18
    Crystal structure of NarGHI mutant NarG-R94S
    1. Bertero MG
    2. Rothery RA
    3. Weiner JH
    4. Strynadka NCJ
    (2009)
    ID 3IR7. Publicly available at the RCSB Protein Data Bank.
  19. 19
  20. 20
    MDT Protein
    1. Schumacher MA
    (2008)
    ID 3DNV. Publicly available at the RCSB Protein Data Bank.
  21. 21
  22. 22
  23. 23
    Crystal structure of the complete initiation complex of RecBCD
    1. Saikrishnan K
    2. Wigley DB
    (2009)
    ID 3K70. Publicly available at the RCSB Protein Data Bank.
  24. 24
  25. 25
  26. 26
  27. 27
  28. 28
    The Crystal Structure of the E. coli Maltose Transporter
    1. Oldham ML
    2. Khare D
    3. Quiocho FA
    4. Davidson AL
    5. Chen J
    (2007)
    ID 2R6G. Publicly available at the RCSB Protein Data Bank.
  29. 29
  30. 30
    Carbamoyl Phosphate Synthetase: Caught in the Act of Glutamine Hydrolysis
    1. Thoden J
    2. Holden H
    (1998)
    ID 1A9X. Publicly available at the RCSB Protein Data Bank.
  31. 31
  32. 32
  33. 33
    Crystal structure of processed TolB in complex with Pal
    1. Sharma A
    2. Bonsor DA
    3. Kleanthous C
    (2009)
    ID 2W8B. Publicly available at the RCSB Protein Data Bank.
  34. 34
    GroEL-GroES-ADP7
    1. Chaudhry C
    2. Horwich AL
    3. Brunger AT
    4. Adams PD
    (2004)
    ID s1SX4. Publicly available at the RCSB Protein Data Bank.
  35. 35
  36. 36
  37. 37
  38. 38
  39. 39
    Complex of FimC, FimF, FimG and FimH
    1. Le Trong I
    2. Aprikian P
    3. Stenkamp RE
    4. Sokurenko EV
    (2009)
    ID 3JWN. Publicly available at the RCSB Protein Data Bank.
  40. 40
  41. 41
  42. 42
  43. 43
  44. 44
  45. 45
  46. 46
    FIMH adhesin-FIMC chaperone complex with D-mannose
    1. Hung CS
    2. Bouckaert J
    (2001)
    ID 1KLF. Publicly available at the RCSB Protein Data Bank.
  47. 47
  48. 48
  49. 49
  50. 50
  51. 51
  52. 52
    Chey-binding domain of chea in complex with chey
    1. Chinardet N
    2. Welch M
    3. Mourey L
    4. Birck C
    5. Samama JP
    (1997)
    ID 1A0O. Publicly available at the RCSB Protein Data Bank.
  53. 53
  54. 54
  55. 55
    Crystal structure of the asymmetric chaperonin complex groel/groes/(ADP)7
    1. Xu Z
    2. Horwich AL
    3. Sigler PB
    (1997)
    ID 1AON. Publicly available at the RCSB Protein Data Bank.
  56. 56
  57. 57
  58. 58
  59. 59
  60. 60
    FimH adhesin Q133N mutant-FimC chaperone complex with methyl-alpha-D-mannose
    1. Hung CS
    2. Bouckaert J
    (2001)
    ID 1KIU. Publicly available at the RCSB Protein Data Bank.
  61. 61
  62. 62
  63. 63
  64. 64
    Crystal Structure of an outward-facing MBP-Maltose transporter complex bound to ADP-BeF3
    1. Oldham M.L
    2. Chen J
    (2010)
    ID 3PUX. Publicly available at the RCSB Protein Data Bank.
  65. 65
  66. 66
    Crystal Structure of an outward-facing MBP-Maltose transporter complex bound to ADP-VO4
    1. Oldham M.L
    2. Chen J
    (2010)
    ID 3PUV. Publicly available at the RCSB Protein Data Bank.
  67. 67
    Crystal Structure of an outward-facing MBP-Maltose transporter complex bound to ADP-AlF4
    1. Oldham M.L
    2. Chen J
    (2010)
    ID 3PUW. Publicly available at the RCSB Protein Data Bank.
  68. 68
  69. 69
  70. 70
  71. 71
  72. 72
  73. 73
    CARBAMOYL PHOSPHATE SYNTHETASE FROM ESCHERICHIA COLI
    1. Thoden J.B
    2. Holden H.M
    3. Wesenberg G
    4. Raushel F.M
    5. Rayment I
    (1997)
    ID 1JDB. Publicly available at the RCSB Protein Data Bank.
  74. 74
  75. 75
  76. 76
  77. 77
  78. 78
  79. 79
    Crystal structure of NarGHI mutant NarG-H49C
    1. Bertero M.G
    2. Rothery R.A
    3. Weiner J.H
    4. Strynadka N.C.J
    (2009)
    ID 3IR5. Publicly available at the RCSB Protein Data Bank.
  80. 80
  81. 81
  82. 82
  83. 83
  84. 84
    Quinol-Fumarate Reductase with Menaquinol Molecules
    1. Iverson T.M
    2. Luna-Chavez C
    3. Croal L.R
    4. Cecchini G
    5. Rees D.C
    (2002)
    ID 1L0V. Publicly available at the RCSB Protein Data Bank.
  85. 85
  86. 86
  87. 87
  88. 88
  89. 89
    Crystal Structure of Activated MPT Synthase
    1. Daniels J.N
    2. Schindelin H
    (2007)
    ID 3BII. Publicly available at the RCSB Protein Data Bank.
  90. 90
    Crystal Structure of NarGH complex
    1. Jormakka M
    2. Richardson D
    3. Byrne B
    4. Iwata S
    (2003)
    ID 1R27. Publicly available at the RCSB Protein Data Bank.
  91. 91
  92. 92
  93. 93
  94. 94
  95. 95
  96. 96
  97. 97
  98. 98
  99. 99
  100. 100
  101. 101
    Crystal structure of the apomolybdo-NarGHI
    1. Rothery R.A
    2. Bertero M.G
    3. Cammack R
    4. Palak M
    5. Blasco F
    6. Strynadka N.C
    7. Weiner J.H
    (2004)
    ID 1SIW. Publicly available at the RCSB Protein Data Bank.
  102. 102
  103. 103
  104. 104
  105. 105
    ClpNS with fragments
    1. Xia D
    2. Maurizi M.R
    3. Guo F
    4. Singh S.K
    5. Esser L
    (2003)
    ID 1R6Q. Publicly available at the RCSB Protein Data Bank.
  106. 106
  107. 107
  108. 108
    Structure of mdt protein
    1. Schumacher M.A
    (2009)
    ID 3HZI. Publicly available at the RCSB Protein Data Bank.
  109. 109
  110. 110
  111. 111
  112. 112
  113. 113
    Orthorhombic Crystal Form of Molybdopterin Synthase
    1. Rudolph M.J
    2. Wuebbens M.M
    3. Turque O
    4. Rajagopalan K.V
    5. Schindelin H
    (2003)
    ID 1NVI. Publicly available at the RCSB Protein Data Bank.
  114. 114
  115. 115
  116. 116
    Crystal structure of Nitrate Reductase A NarGHI, from Escherichia coli
    1. Bertero M.G
    2. Strynadka N.C.J
    (2003)
    ID 1Q16. Publicly available at the RCSB Protein Data Bank.
  117. 117
  118. 118
  119. 119
  120. 120
  121. 121
  122. 122
  123. 123
  124. 124
  125. 125
  126. 126
  127. 127
  128. 128
  129. 129
  130. 130
  131. 131
  132. 132
  133. 133
  134. 134
  135. 135
  136. 136
    The crystal structure of the NarGHI mutant NarH C16A
    1. Bertero M.G
    2. Rothery R.A
    3. Weiner J.H
    4. Strynadka N.C.J
    (2008)
    ID 3EGW. Publicly available at the RCSB Protein Data Bank.
  137. 137
  138. 138
  139. 139
  140. 140
  141. 141
  142. 142
  143. 143
    Structure of the E.coli F1-ATP synthase inhibited by subunit Epsilon
    1. Cingolani G
    2. Duncan T.M
    (2010)
    ID 3OAA. Publicly available at the RCSB Protein Data Bank.
  144. 144
  145. 145
  146. 146
  147. 147
  148. 148
  149. 149
    MOLYBDOPTERIN SYNTHASE (MOAD/MOAE)
    1. Rudolph M.J
    2. Wuebbens M.M
    3. Rajagolpalan K.V
    4. Schindelin H
    (2000)
    ID 1FM0. Publicly available at the RCSB Protein Data Bank.
  150. 150
  151. 151
  152. 152
  153. 153
  154. 154
  155. 155
    Crystal structure of NarGHI mutant NarG-H49S
    1. Bertero M.G
    2. Rothery R.A
    3. Weiner J.H
    4. Strynadka N.C.J
    (2009)
    ID 3IR6. Publicly available at the RCSB Protein Data Bank.
  156. 156
  157. 157
  158. 158
  159. 159
  160. 160
  161. 161
  162. 162
  163. 163
    ATCASE Y165F MUTANT
    1. Ha Y
    2. Allewell N.M
    (1998)
    ID 9ATC. Publicly available at the RCSB Protein Data Bank.
  164. 164
  165. 165
  166. 166
  167. 167
  168. 168
  169. 169
  170. 170
  171. 171
  172. 172
    Crystal structure of groEL-groES
    1. Chaudhry C
    2. Farr G.W
    3. Todd M.J
    4. Rye H.S
    5. Brunger A.T
    6. Adams P.D
    7. Horwich A.L
    8. Sigler P.B
    (2003)
    ID 1PCQ. Publicly available at the RCSB Protein Data Bank.
  173. 173
  174. 174
  175. 175
  176. 176
  177. 177
    MOLYBDOPTERIN SYNTHASE (MOAD/MOAE)
    1. Rudolph M.J
    2. Wuebbens M.M
    3. Rajagolpalan K.V
    4. Schindelin H
    (2000)
    ID 1FMA. Publicly available at the RCSB Protein Data Bank.
  178. 178
  179. 179
  180. 180
  181. 181
  182. 182
    Crystal Structure of the MukE-MukF Complex
    1. Suh M.K
    2. Ku B
    3. Ha N.C
    4. Woo J.S
    5. Oh B.H
    (2008)
    ID 3EUH. Publicly available at the RCSB Protein Data Bank.
  183. 183
  184. 184
  185. 185
  186. 186
  187. 187
  188. 188
  189. 189
    Crystal structure of SufC-SufD complex involved in the iron-sulfur cluster biosynthesis
    1. Wada K
    (2008)
    ID 2ZU0. Publicly available at the RCSB Protein Data Bank.
  190. 190
  191. 191
  192. 192
  193. 193
  194. 194
    A1C12 SUBCOMPLEX OF F1FO ATP SYNTHASE
    1. Rastogi V.K
    2. Girvin M.E
    (1999)
    ID 1C17. Publicly available at the RCSB Protein Data Bank.
  195. 195
    Crystal structure of the CusBA heavy-metal efflux complex from Escherichia E. coli
    1. Su C.-C
    (2010)
    ID 3NE5. Publicly available at the RCSB Protein Data Bank.
  196. 196
  197. 197
  198. 198
    Crystal structure of TolB/Pal complex
    1. Grishkovskaya I
    2. Bonsor D.A
    3. Kleanthous C
    4. Dodson E.J
    (2006)
    ID 2HQS. Publicly available at the RCSB Protein Data Bank.
  199. 199
  200. 200
  201. 201
  202. 202
  203. 203
  204. 204
  205. 205
    E. coli Quinol fumarate reductase FrdA T234A mutation
    1. Tomasiak T.M
    2. Maklashina E
    3. Cecchini G
    4. Iverson T.M
    (2008)
    ID 3CIR. Publicly available at the RCSB Protein Data Bank.
  206. 206
  207. 207
  208. 208
  209. 209
  210. 210
  211. 211
    Crystal structure of methionine importer MetNI
    1. Rees D.C
    2. Kaiser J.T
    3. Kadaba N.S
    4. Johnson E
    5. Lee A.T
    (2008)
    ID 3DHW. Publicly available at the RCSB Protein Data Bank.
  212. 212
  213. 213
  214. 214
    CRYSTAL STRUCTURE ANALYSIS OF ClpSN WITH TRANSITION METAL ION BOUND
    1. Guo F
    2. Esser L
    3. Singh S.K
    4. Maurizi M.R
    5. Xia D
    (2002)
    ID 1MBX. Publicly available at the RCSB Protein Data Bank.
  215. 215
  216. 216
  217. 217
  218. 218
  219. 219
    Crystal Structure Analysis of ClpSN heterodimer
    1. Guo F
    2. Esser L
    3. Singh S.K
    4. Maurizi M.R
    5. Xia D
    (2002)
    ID 1MBU. Publicly available at the RCSB Protein Data Bank.
  220. 220
    CRYSTAL STRUCTURE ANALYSIS OF ClpSN HETERODIMER TETRAGONAL FORM
    1. Guo F
    2. Esser L
    3. Singh S.K
    4. Maurizi M.R
    5. Xia D
    (2002)
    ID 1MBV. Publicly available at the RCSB Protein Data Bank.
  221. 221
  222. 222
    Crystal Structure of ET-EHred-5-CH3-THF complex
    1. Okamura-Ikeda K
    2. Hosaka H
    (2009)
    ID 3A8I. Publicly available at the RCSB Protein Data Bank.
  223. 223
    Crystal Structure of ET-EHred complex
    1. Okamura-Ikeda K
    2. Hosaka H
    (2009)
    ID 3A8J. Publicly available at the RCSB Protein Data Bank.
  224. 224
    Crystal Structure of ETD97N-EHred complex
    1. Okamura-Ikeda K
    2. Hosaka H
    (2009)
    ID 3A8K. Publicly available at the RCSB Protein Data Bank.
  225. 225
  226. 226
  227. 227
  228. 228
  229. 229
  230. 230
  231. 231
  232. 232
    Bacterial ABC Transporter Involved in B12 Uptake
    1. Locher K.P
    2. Lee A.T
    3. Rees D.C
    (2002)
    ID 1L7V. Publicly available at the RCSB Protein Data Bank.
  233. 233
    COMPLEX OF GAMMA/EPSILON ATP SYNTHASE FROM E.COLI
    1. Wilce M.C.J
    2. Rodgers A.J.W
    (2000)
    ID 1FS0. Publicly available at the RCSB Protein Data Bank.
  234. 234
  235. 235
  236. 236
  237. 237
  238. 238
  239. 239
  240. 240
  241. 241
  242. 242
  243. 243
  244. 244
  245. 245
  246. 246
  247. 247
  248. 248
  249. 249
    FORMATE DEHYDROGENASE N FROM E. COLI
    1. Jormakka M
    2. Tornroth S
    3. Byrne B
    4. Iwata S
    (2002)
    ID 1KQG. Publicly available at the RCSB Protein Data Bank.
  250. 250
    FORMATE DEHYDROGENASE N FROM E. COLI
    1. Jormakka M
    2. Tornroth S
    3. Byrne B
    4. Iwata S
    (2002)
    ID 1KQF. Publicly available at the RCSB Protein Data Bank.
  251. 251
  252. 252
  253. 253
  254. 254
    Crystal structure of GroEL14-GroES7-(ADP-AlFx)7
    1. Chaudhry C
    2. Horwich A.L
    3. Brunger A.T
    4. Adams P.D
    (2004)
    ID 1SVT. Publicly available at the RCSB Protein Data Bank.
  255. 255
  256. 256
  257. 257
  258. 258
    RecBCD: DNA complex
    1. Singleton M.R
    2. Dillingham M.S
    3. Gaudier M
    4. Kowalczykowski S.C
    5. Wigley D.B
    (2004)
    ID 1W36. Publicly available at the RCSB Protein Data Bank.
  259. 259
  260. 260
  261. 261
    Crystal structure of HypE-HypF complex
    1. Shomura Y
    2. Higuchi Y
    (2012)
    ID 3VTI. Publicly available at the RCSB Protein Data Bank.
  262. 262
  263. 263
  264. 264
  265. 265
  266. 266
  267. 267
  268. 268
  269. 269
    ASPARTATE TRANSCARBOMYLASE REGULATORY CHAIN MUTANT (T82A)
    1. Williams M.K
    2. Stec B
    3. Kantrowitz E.R
    (1998)
    ID 1NBE. Publicly available at the RCSB Protein Data Bank.

Additional files

Supplementary file 1

Benchmark data set and results.

https://doi.org/10.7554/eLife.03430.024
Supplementary file 2

De novo prediction data set and results.

https://doi.org/10.7554/eLife.03430.025
Supplementary file 3

Docking results.

https://doi.org/10.7554/eLife.03430.026
Supplementary file 4

Predicted inter-ECs for complexes in de novo prediction data set with EVcomplex score ≥0.8.

https://doi.org/10.7554/eLife.03430.027
Supplementary file 5

ATP synthase interaction predictions.

https://doi.org/10.7554/eLife.03430.028
Supplementary file 6

Comparison of ATP synthase EVcomplex predictions of a and b subunit with cross-linking studies.

https://doi.org/10.7554/eLife.03430.029
Supplementary file 7

PDB identifiers used for comparison of predicted evolutionary couplings to known 3D structures.

https://doi.org/10.7554/eLife.03430.030

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