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. 2006 Jul 12:7:340.
doi: 10.1186/1471-2105-7-340.

Quaternary structure predictions of transmembrane proteins starting from the monomer: a docking-based approach

D Casciari  1 , M Seeber, F Fanelli
Affiliations

Quaternary structure predictions of transmembrane proteins starting from the monomer: a docking-based approach

D Casciari et al. BMC Bioinformatics. .

Abstract

Background: We introduce a computational protocol for effective predictions of the supramolecular organization of integral transmembrane proteins, starting from the monomer. Despite the demonstrated constitutive and functional importance of supramolecular assemblies of transmembrane subunits or proteins, effective tools for structure predictions of such assemblies are still lacking. Our computational approach consists in rigid-body docking samplings, starting from the docking of two identical copies of a given monomer. Each docking run is followed by membrane topology filtering and cluster analysis. Prediction of the native oligomer is therefore accomplished by a number of progressive growing steps, each made of one docking run, filtering and cluster analysis. With this approach, knowledge about the oligomerization status of the protein is required neither for improving sampling nor for the filtering step. Furthermore, there are no size-limitations in the systems under study, which are not limited to the transmembrane domains but include also the water-soluble portions.

Results: Benchmarks of the approach were done on ten homo-oligomeric membrane proteins with known quaternary structure. For all these systems, predictions led to native-like quaternary structures, i.e. with Calpha-RMSDs lower than 2.5 A from the native oligomer, regardless of the resolution of the structural models.

Conclusion: Collectively, the results of this study emphasize the effectiveness of the prediction protocol that will be extensively challenged in quaternary structure predictions of other integral membrane proteins.

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Figures

Figure 1
Figure 1
Flowchart of the docking-based stepwise oligomerization approach. The quaternary structure prediction approach consists in a number of dense docking samplings, starting from the docking of two identical copies of a given monomer. Each docking run is followed by membrane topology filtering and cluster analysis. Thus, prediction of the native oligomer is accomplished by a number of progressive growing steps, each made of one docking run, filtering and cluster analysis. For each stepwise quaternary structure prediction, the docking runs that succeeded the first one were carried out by using the original monomer as a probe and the intermediate oligomer as a target.
Figure 2
Figure 2
Native and native-like structures of tetrameric KcsA. (a) View of the crystal structure seen from the extracellular side; the monomers are differently colored. (b) and (c) The superimposition between native (green color) and the best native-like (violet color) structures is shown. The native-like structure shown in this figure, i.e. the A-Bs1-Cs500-Ds2 tetramer, has been achieved through a dipole moment-based reorientation approach (see Table 1 and Figure 6). In panel (b) the superimposed structures are seen from the extracellular side, whereas in panel (c) the structures are seen in a direction parallel to the membrane surface. Drawings were done by means of the software PYMOL 0.98 [39].
Figure 3
Figure 3
Native and best native-like structures of pentameric MscL. The best predicted native-like pentamer (violet color) is the one encoded as A-Bs8-Cs1-Ds1-Es6 (see Table 1 and Figure 7). The description of this figure is like that of Figure 2.
Figure 4
Figure 4
Native and best native-like structures of eptameric MscS. The best predicted native-like eptamer (violet color) is the one encoded as A-Bs3-Cs1-Ds1-Es6-Fs1-Gs1 (see Table 1 and Figure 8). The description of this figure is like that of Figure 2.
Figure 5
Figure 5
Native and native-like structures of trimeric BRD. The predicted native-like eptamer (violet color) is the one encoded as A-Bs162-Cs14 (see Table 1 and Figure 9). The description of this figure is like that of Figure 2.
Figure 6
Figure 6
Prediction paths for KcsA. Each of the three different growing paths ((a), (b) and (c)) is characterized by selection, at each growing step, of the best scored solution within the most populated cluster/s, characterized also by similar and significantly low MemTop index. The number of solutions filtered at each step is reported under the arrow. The circle on the arrow indicates the probe, whereas the circles that precede the arrow are the targets. The monomers that constitute these targets are indicated by gray circles except for the last added monomer/s, which are indicated by white circle/s and by the solution number in the ZDOCK output list. The final oligomer is indicated by a string of letters and characters in a way that each subunit is associated with the docking solution. In detail, the upper case letter indicates the subunit, whereas the letter "s" followed by a number indicates the solution number in the ZDOCK output list. Finally, the Cα-RMSD (Å) between native and predicted quaternary structures is also reported. All the amino acid residues have been included in Cα-RMSD calculations.
Figure 7
Figure 7
Prediction paths for MscL. See Figure 6 for the description of this figure.
Figure 8
Figure 8
Prediction paths for MscS. See Figure 6 for the description of this figure.
Figure 9
Figure 9
Prediction path for BRD (top) and for AmtB and AcrB (bottom). The description of this figure is the same as that in Figure 6. For BRD, only one growing path has been pursued. In contrast, for quaternary structure predictions of AmtB and AcrB, the growing paths (a), (b) and (c) were probed. Black bold labels refer to AmtB, whereas gray bold labels refer to AcrB predictions.
Figure 10
Figure 10
Superimposition between native (green color) and the best native-like (violet color) oligomeric structures of: (a) AQP1 (PDB code: 1J4N; Cα-RMSD = 1.31 Å; best predicted tetramer: A-Bs2-Cs1-Ds1), (b) GlpF (PDB code: 1FX8; Cα-RMSD = 1.11 Å; best predicted tetramer: A-Bs2-Cs1-Ds1), (c) KirBac1 (PDB code: 1P7B; Cα-RMSD = 1.47 Å; best predicted tetramer: A-Bs3-Cs1-Ds3), (d) AmtB (PDB code: 1U77; Cα-RMSD = 0.75 Å; best predicted trimer: A-Bs1-Cs1), (e) AcrB (PDB code: 1IGW; Cα-RMSD = 1.56 Å; best predicted trimer: A-Bs4-Cs1), and (f) BtuCD (PDB code: 1L7V; Cα-RMSD = 0.63 Å). For BtuCD, the native-like structure shown in this figure, i.e. the A-Bs1678 dimer, has been achieved through a dipole moment-based reorientation approach. The oligomers are seen from the extracellular side in a direction perpendicular to the putative membrane surface.
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