A structural biology community assessment of AlphaFold 2 applications

Abstract

Most proteins fold into 3D structures that determine how they function and orchestrate the biological processes of the cell. Recent developments in computational methods have led to protein structure predictions that have reached the accuracy of experimentally determined models. While this has been independently verified, the implementation of these methods across structural biology applications remains to be tested. Here, we evaluate the use of AlphaFold 2 (AF2) predictions in the study of characteristic structural elements; the impact of missense variants; function and ligand binding site predictions; modelling of interactions; and modelling of experimental structural data. For 11 proteomes, an average of 25% additional residues can be confidently modelled when compared to homology modelling, identifying structural features rarely seen in the PDB. AF2-based predictions of protein disorder and protein complexes surpass state-of-the-art tools and AF2 models can be used across diverse applications equally well compared to experimentally determined structures, when the confidence metrics are critically considered. In summary, we find that these advances are likely to have a transformative impact in structural biology and broader life science research.

The structural coverage of the human proteome before and after AlphaFold

“…Additionally, for a more straightforward interpretation of the results, we set in this study 3 different levels of protein structural coverage according to 3 ranges of sequence identity percentages between a protein and a PDB chain. The ranges are: >95%, which includes the real structure of the protein; 95-50%, which contains useful templates to study the impact of mutations[25]; and 50-20%, which contemplates structural coverage of distant related proteins assuming that structure is more conserved than sequence. With this definition our results show that the current structural coverage of the human proteome is 48% of all human protein residues (Figure 1c) when sequence identity ≥ 20%.…”

AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models

“…Residues with 70 > pLDDT ≥ 50 have low confidence, and residues with pLDDT < 50 correspond to very low confidence ( 13 ). It was recently described that very low confidence pLDDT scores correlate with high propensities for intrinsic disorder ( 17 ).…”

Modeling Alternate Conformations with Alphafold2 via Modification of the Multiple Sequence Alignment

“…Recent reports have utilized AF2 models and existing paradigms to ascertain the potential effect of a mutation without a discernible correlation. 24,25 Here the structures of the mutant protein lead to an increase in disorder or altered conformations. The challenge will be in devising metrics to quantitate and evaluate the effect of the mutation on the structure relative to the wild type structure.…”