2.5 | Macromolecular Ensembles
Previously, CASP has assumed that there is only one relevant structure
of a protein to compute, and that structure is represented by a single
experimental structure. Increasingly, experimental methods provide more
than one structure and computational methods should be able to produce
all of these. In this CASP, we introduced an ensembles category with
targets that have multiple experimentally observed conformations. As the
ensembles evaluation paper discusses (9), there are still very limited
experimental data of this type and even when there are data it is not
always clear what a computational method should reasonably be expected
to deliver. Nevertheless, the CASP15 results do provide preliminary
insight into the abilities of computational methods in this area.
There are a number of encouraging results. Of particular note are
reproduction of a domain-swap conformational change induced by a single
mutation, sampling of three different conformations of an ABC
transporter in the presence of different ligands; sampling of kinase
substructures observed under different conditions; and sampling of
alternative conformations of a small protein found in two different
crystal forms. On the other hand, modeling of an RNA folding
intermediate proved too difficult, as did different states of a Holliday
junction complex. However, these failures may reflect the intrinsic
difficulties of the targets as much as sampling deficiencies. The
successful methods again used variants of AlphaFold2, with enhanced
sampling, including adjustment of the multiple sequence alignment. In
this respect, strategies are similar to those used for tertiary
structure and protein assembly modeling, though details differ. Many
preprints are appearing on improved ensemble modeling methods, so that
we expect substantial advances in the next CASP round.