Free docking
Our free docking results show similar trends as in previous CASP and CAPRI experiments (Fig. 5, Supplementary Table S3)17. First, the IPS values are sometimes much higher than ICS. This indicates that the residues mediating protein-protein binding are predicted better than the mutual subunit orientation defining the exact contacts at the interaction interface. Another observation is that the accuracy of subunits matters a lot when docking modeled protein structures. We did not produce any acceptable accuracy models when we were starting from subunit structures of lower accuracy (lDDT < 0.4 or TM-score < 0.5). It is also important to note that the opposite is not necessarily true. Accurate models of individual subunits do not guarantee accurate docking models.
The most successful docking results were obtained for H1081v0, T1083 (Fig. 6) and T1084. Interestingly, in the cases of T1083 and T1084 the free docking models were better than the template-based models, but the reasons for this are not clear. H1081 was a large target, where two decameric rings had to be docked, and for that we developed a custom procedure. The homology models of decameric rings were aligned on the axis perpendicular to the ring plane and then pushed to each other (using 1 Å steps) and rotated around the axis (using 2 degrees steps), saving every distinct arrangement. Afterwards all obtained models were relaxed, scored and ranked. This custom “two-ring docking” procedure resulted in surprisingly good models.
The modeling of other docking targets was less successful (Fig. 7) illustrating common problems related to the monomer model accuracy and scoring. For example, in the monomer structure of T1054 which we used for docking, the position of N-terminal helix is not compatible with the dimeric structure. The helix is too well packed against the subunit structure, occupying the place of a helix from another subunit in the dimer (Fig. 7A, B). Therefore, it was impossible to obtain a correct docking model starting from such a monomer. Interestingly, when during the post-CASP analysis we repeated the docking experiment using the same monomer model, but without the N-terminal helix, the docking was highly successful (Fig. 7C). Of note, the structure and the oligomeric state of this protein are dynamic. It exists as a monomer, a dimer or a decamer in solution, and the dimer observed in the crystal might represent an intermediate state in decamerization42.
In our best model for heterodimeric target H1065 one of the subunits is rotated ~180 degrees compared to the experimental structure (Fig. 7E). Again, the interface patch is identified correctly while the interface contacts and subunit orientation are different. Both monomer models are fairly accurate (lDDT > 0.65, CAD-score > 0.7, TM-score > 0.8), therefore, their accuracy probably is not the reason of incorrect docking (Fig 7D). However, scoring is really problematic for H1065: both the global and the interface VoroMQA scores of the experimental structure and the model are highly similar (global scores: 0.70 vs. 0.68, interface energy: -354 vs. -388 for target and model, respectively). In other words, had the experimental structure been present together with all the models it would not necessarily have been selected.