Assessment of protein assembly prediction in CASP13

Abstract

We present the assembly category assessment in the 13th edition of the CASP community-wide experiment. For the second time, protein assemblies constitute an independent assessment category. Compared to the last edition we see a clear uptake in participation, more oligomeric targets released, and consistent, albeit modest, improvement of the predictions quality. Looking at the tertiary structure predictions, we observe that ignoring the oligomeric state of the targets hinders modeling success. We also note that some contact prediction groups successfully predicted homomeric interfacial contacts, though it appears that these predictions were not used for assembly modeling. Homology modeling with sizeable human intervention appears to form the basis of the assembly prediction techniques in this round of CASP. Future developments should see more integrated approaches where subunits are modeled in the context of the assemblies they form.

Keywords: CASP; protein assembly; protein interfaces; structure prediction.

FIGURE 1

Score correlations. A heat map with correlations among all relevant scores used in the predictioncenter.org web site. The “local” block of scores captures interface features, the “global” block captures features of the whole assembly.

FIGURE 2

Per-target score distributions and comparison to the baseline (naïve) values, if present. The targets for which the median prediction is worse than the baseline in each score are labeled in red. The naïve baseline comes from the Seok-naive_assembly method, which employs HHsearch to find the best templates for homo-oligomers, then builds an alignment per template with HHalign and finally calculates several models with Modeller [46], from which the lowest energy (as calculated by Modeller) model is selected.

FIGURE 3

Performance comparison between CASP13 and CASP12. 5 top predictions per target (maximum 1 per group) were selected for each score from CASP12 and CASP13 submissions. The scores were matched by percentiles and plotted as CASP12 (x axis) vs. CASP13 (y axis). Values above the diagonal correspond to improvement in CASP13.

FIGURE 4

Group rankings in the assembly category. The groups are sorted by the sum of Z -scores for all difficulty classes. The error bars are obtained by iteratively excluding every target from each difficulty class and recalculating the cumulative Z -scores. The server groups are labeled in violet.

FIGURE 5

Importance of quaternary modelling. A) Targets T0973, T0991 and T0998 with very large dimeric interfaces and the main hydrophobic core split at the interface. The best regular prediction GDT_TS scores for their corresponding monomeric evaluation units were: 82.62 for T0973-D1, 37.16 for T0991-D1 and 35.54 for T0998-D1. B) Trimeric part of target H0953 showing the intertwined beta-strand geometry in the C-terminal half of the fold.

FIGURE 6

Sequence-based prediction of homomeric interface contacts for three CASP13 FM targets: A) interdigitated trimer T0953s1 and prediction by group RR106; B) dimeric interface (isologous) of T0968s2 and prediction by group RR036; and C) hexameric subunit T1022s1 and prediction by group RR164. Contacts in the target assembly are shown in the upper-right of the matrix and predicted contacts are shown in the lower-left, with transparency levels proportional to the contact rank. Contacts are classified based on the nature of the interaction: interface (orange), tertiary (blue), tertiary and interface (shared, purple) or prediction false positives (no contact, black).

FIGURE 7

Prediction highlights. A) The homodimeric target T0976 and the monomeric template that matches the global arrangement of the 4 domains, B) Homodimeric target T1001 and the template PDB entry 5LLW, a much larger protein, the highlighted central domain has a very close tertiary structure and a similar interface region. C) The A2B2 heterotetramer T0968 with a main homomeric interface (cyan and yellow chains) via beta pairing, composing a large beta sandwich. The other subunit attaches on either side of the beta sheets.