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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 14 targets and high accuracy (DockQ≥0.8) on 6 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 4,433 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 67% of cases, and produce high accuracy predictions (DockQ≥0.8) in 23% of cases, an improvement of +25 and +11 percentage points over the flexible linker modification of AlphaFold [4] respectively. For homomeric interfaces we successfully predict the interface in 69% of cases, and produce high accuracy predictions in 34% of cases, an improvement of +5 percentage points in both instances.

Protein structure prediction aims to determine the three-dimensional shape of a protein from its amino acid sequence 1. This problem is of fundamental importance to biology as the structure of a protein largely determines its function 2 but can be hard to determine experimentally. In recent years, considerable progress has been made by leveraging genetic information: analysing the co-variation of homologous sequences can allow one to infer which amino acid residues are in contact, which in turn can aid structure prediction 3. In this work, we show that we can train a neural network to accurately predict the distances between pairs of residues in a protein which convey more about structure than contact predictions. With this information we construct a potential of mean force 4 that can accurately describe the shape of a protein. We find that the resulting potential can be optimised by a simple gradient descent algorithm, to realise structures without the need for complex sampling procedures. The resulting system, named AlphaFold, has been shown to achieve high accuracy, even for sequences with relatively few homologous sequences. In the most recent Critical Assessment of Protein Structure Prediction 5 (CASP13), a blind assessment of the state of the field of protein structure prediction, AlphaFold created high-accuracy structures (with TM-scores † of 0.7 or higher) for 24 out of 43 free modelling domains whereas the next best method, using sampling and contact information, achieved such accuracy for only 14 out of 43 domains. AlphaFold represents a significant advance in protein structure prediction. We expect the increased accuracy of structure predictions for proteins to enable insights in understanding the function and malfunction of these proteins, especially in cases where no homologous proteins have been experimentally determined 7. Proteins are at the core of most biological processes. Since the function of a protein is dependent on its structure, understanding protein structure has been a grand challenge in biology for decades. While several experimental structure determination techniques have been developed † Template Modelling score 6 , between 0 and 1, measures the degree of match of the overall (backbone) shape of a proposed structure to a native structure.

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Artificial Neural Networks are powerful function approximators capable of modelling solutions to a wide variety of problems, both supervised and unsupervised. As their size and expressivity increases, so too does the variance of the model, yielding a nearly ubiquitous overfitting problem. Although mitigated by a variety of model regularisation methods, the common cure is to seek large amounts of training data-which is not necessarily easily obtained-that sufficiently approximates the data distribution of the domain we wish to test on. In contrast, logic programming methods such as Inductive Logic Programming offer an extremely data-efficient process by which models can be trained to reason on symbolic domains. However, these methods are unable to deal with the variety of domains neural networks can be applied to: they are not robust to noise in or mislabelling of inputs, and perhaps more importantly, cannot be applied to non-symbolic domains where the data is ambiguous, such as operating on raw pixels. In this paper, we propose a Differentiable Inductive Logic framework, which can not only solve tasks which traditional ILP systems are suited for, but shows a robustness to noise and error in the training data which ILP cannot cope with. Furthermore, as it is trained by backpropagation against a likelihood objective, it can be hybridised by connecting it with neural networks over ambiguous data in order to be applied to domains which ILP cannot address, while providing data efficiency and generalisation beyond what neural networks on their own can achieve.

We describe AlphaFold, the protein structure prediction system that was entered by the group A7D in CASP13. Submissions were made by three free‐modeling (FM) methods which combine the predictions of three neural networks. All three systems were guided by predictions of distances between pairs of residues produced by a neural network. Two systems assembled fragments produced by a generative neural network, one using scores from a network trained to regress GDT_TS. The third system shows that simple gradient descent on a properly constructed potential is able to perform on par with more expensive traditional search techniques and without requiring domain segmentation. In the CASP13 FM assessors' ranking by summed z‐scores, this system scored highest with 68.3 vs 48.2 for the next closest group (an average GDT_TS of 61.4). The system produced high‐accuracy structures (with GDT_TS scores of 70 or higher) for 11 out of 43 FM domains. Despite not explicitly using template information, the results in the template category were comparable to the best performing template‐based methods.

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-toend 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.

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