Michał Zieliński

Abstract The introduction of AlphaFold 2 1 has spurred a revolution in modelling the structure of proteins and their interactions, enabling a huge range of applications in protein modelling and design 2–6 . Here we describe our AlphaFold 3 model with a substantially updated diffusion-based architecture that is capable of predicting the joint structure of complexes including proteins, nucleic acids, small molecules, ions and modified residues. The new AlphaFold model demonstrates substantially improved accuracy over many previous specialized tools: far greater accuracy for protein–ligand interactions compared with state-of-the-art docking tools, much higher accuracy for protein–nucleic acid interactions compared with nucleic-acid-specific predictors and substantially higher antibody–antigen prediction accuracy compared with AlphaFold-Multimer v.2.3 7,8 . Together, these results show that high-accuracy modelling across biomolecular space is possible within a single unified deep-learning framework.

While the vast majority of well-structured single protein chains can now be predicted to high accuracy due to the recent AlphaFold [1] model, the prediction of multi-chain protein complexes remains a challenge in many cases. In this work, we demonstrate that an AlphaFold model trained specifically for multimeric inputs of known stoichiometry, which we call AlphaFold-Multimer, significantly increases accuracy of predicted multimeric interfaces over input-adapted single-chain AlphaFold while maintaining high intra-chain accuracy. On a benchmark dataset of 17 heterodimer proteins without templates (introduced in [2]) we achieve at least medium accuracy (DockQ [3] ≥ 0.49) on 13 targets and high accuracy (DockQ ≥ 0.8) on 7 targets, compared to 9 targets of at least medium accuracy and 4 of high accuracy for the previous state of the art system (an AlphaFold-based system from [2]). We also predict structures for a large dataset of 4,446 recent protein complexes, from which we score all non-redundant interfaces with low template identity. For heteromeric interfaces we successfully predict the interface (DockQ ≥ 0.23) in 70% of cases, and produce high accuracy predictions (DockQ ≥ 0.8) in 26% of cases, an improvement of +27 and +14 percentage points over the flexible linker modification of AlphaFold [4] respectively. For homomeric inter-faces we successfully predict the interface in 72% of cases, and produce high accuracy predictions in 36% of cases, an improvement of +8 and +7 percentage points respectively.

Abstract Protein structures can provide invaluable information, both for reasoning about biological processes and for enabling interventions such as structure-based drug development or targeted mutagenesis. After decades of effort, 17% of the total residues in human protein sequences are covered by an experimentally determined structure 1 . Here we markedly expand the structural coverage of the proteome by applying the state-of-the-art machine learning method, AlphaFold 2 , at a scale that covers almost the entire human proteome (98.5% of human proteins). The resulting dataset covers 58% of residues with a confident prediction, of which a subset (36% of all residues) have very high confidence. We introduce several metrics developed by building on the AlphaFold model and use them to interpret the dataset, identifying strong multi-domain predictions as well as regions that are likely to be disordered. Finally, we provide some case studies to illustrate how high-quality predictions could be used to generate biological hypotheses. We are making our predictions freely available to the community and anticipate that routine large-scale and high-accuracy structure prediction will become an important tool that will allow new questions to be addressed from a structural perspective.

Abstract We describe the operation and improvement of AlphaFold, the system that was entered by the team AlphaFold2 to the “human” category in the 14th Critical Assessment of Protein Structure Prediction (CASP14). The AlphaFold system entered in CASP14 is entirely different to the one entered in CASP13. It used a novel end‐to‐end deep neural network trained to produce protein structures from amino acid sequence, multiple sequence alignments, and homologous proteins. In the assessors' ranking by summed z scores (>2.0), AlphaFold scored 244.0 compared to 90.8 by the next best group. The predictions made by AlphaFold had a median domain GDT_TS of 92.4; this is the first time that this level of average accuracy has been achieved during CASP, especially on the more difficult Free Modeling targets, and represents a significant improvement in the state of the art in protein structure prediction. We reported how AlphaFold was run as a human team during CASP14 and improved such that it now achieves an equivalent level of performance without intervention, opening the door to highly accurate large‐scale structure prediction.

In our original article, we provided an extensive