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.