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.