Abstract
Computing protein structure from amino acid sequence information has
been a long-standing grand challenge. CASP (Critical Assessment of
Structure Prediction) conducts community experiments aimed at advancing
solutions to this and related problems. Experiments are conducted every
two years. The 2020 experiment (CASP14) saw major progress, with the
second generation of deep learning methods delivering accuracy
comparable with experiment for many single proteins. There is an
expectation that these methods will have much wider application in
computational structural biology. Here we summarize results from the
most recent experiment, CASP15, in 2022, with an emphasis on new deep
learning-driven progress. Other papers in this special issue of Proteins
provide more detailed analysis. For single protein structures, the
AlphaFold2 deep learning method is still superior to other approaches,
but there are two points of note. First, although AlphaFold2 was the
core of all the most successful methods, there was a wide variety of
implementation and combination with other methods. Second, using the
standard AlphaFold2 protocol and default parameters only produces the
highest quality result for about two thirds of the targets, and more
extensive sampling is required for the others. The major advance in this
CASP is the enormous increase in the accuracy of computed protein
complexes, achieved by the use of deep learning methods, although
overall these do not fully match the performance for single proteins.
Here too, AlphaFold2 based method perform best, and again more extensive
sampling than the defaults is often required. Also of note are the
encouraging early results on the use of deep learning to compute
ensembles of macromolecular structures. Critically for the usability of
computed structures, for both single proteins and protein complexes,
deep learning derived estimates of both local and global accuracy are of
high quality, however the estimates in interface regions are slightly
less reliable. CASP15 also included computation of RNA structures for
the first time. Here, the classical approaches produced better agreement
with experiment than the new deep learning ones, and accuracy is
limited. Also, for the first time, CASP included the computation of
protein-ligand complexes, an area of special interest for drug design.
Here too, classical methods were still superior to deep learning ones.
Many new approaches were discussed at the CASP conference, and it is
clear methods will continue to advance.