Template-based modeling
As the structures of protein complexes are often evolutionary conserved9, template-based modeling is currently the most reliable method to model them. Straightforward multimeric comparative modeling resulted in medium to high accuracy models for 8 of 11 CASP14 targets. Template-based docking also resulted in medium accuracy models for two targets. Thus, if reliable templates were available the template-based approach worked well for both homomers and heteromers.
Identifying the correct template having the same oligomeric state is the key to successful modeling of protein complexes15–17, 36. Ambiguous oligomeric state of templates may be the reason why we failed to model T1034, for which we used templates having different oligomeric states.
In CASP14 we had additional examples demonstrating the limitations of template-based modeling for protein complexes. One such example, H1036, represents a trimeric viral protein bound to an antibody. Our models were based on homologous trimer structures bound to antibodies. This resulted in good models of homotrimer interfaces, but the antibody was bound to a completely different epitope (Fig. S7). This incorrectly predicted interface is not surprising bearing in mind the nature of antibody-antigen interactions. The binding site in the antibody (paratope) is formed by hypervariable loop regions, and the antigen binding site (epitope) can be anywhere on the protein surface41.
Our results for T1099 show another limitation of template-based approach for protein complexes. This target is a large viral capsid, yet modeling its structure can be reduced to a problem of predicting a homotetramer (T1099v0) having two different interaction interfaces (T1099v1 and T1099v2). Our models contained high-accuracy interface 2, yet the interface 1 was incorrect (Fig. S8). The reason of this failure was the large insertion in the target interface, compared to the template structures.