The introduction of AlphaFold 21 has spurred a revolution in modelling the structure of proteins and their interactions, enabling a huge range of applications in protein modelling and design2-6. 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.2.37,8. Together, these results show that high-accuracy modelling across biomolecular space is possible within a single unified deep-learning framework.

The AlphaFold Protein Structure Database (AlphaFold DB, https://alphafold.ebi.ac.uk) is an openly accessible, extensive database of high-accuracy protein-structure predictions. Powered by AlphaFold v2.0 of DeepMind, it has enabled an unprecedented expansion of the structural coverage of the known protein-sequence space. AlphaFold DB provides programmatic access to and interactive visualization of predicted atomic coordinates, per-residue and pairwise model-confidence estimates and predicted aligned errors. The initial release of AlphaFold DB contains over 360,000 predicted structures across 21 model-organism proteomes, which will soon be expanded to cover most of the (over 100 million) representative sequences from the UniRef90 data set.

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.

Proteins are essential to life, and understanding their structure can facilitate a mechanistic understanding of their function. Through an enormous experimental effort 1–4 , the structures of around 100,000 unique proteins have been determined 5 , but this represents a small fraction of the billions of known protein sequences 6,7 . Structural coverage is bottlenecked by the months to years of painstaking effort required to determine a single protein structure. Accurate computational approaches are needed to address this gap and to enable large-scale structural bioinformatics. Predicting the three-dimensional structure that a protein will adopt based solely on its amino acid sequence—the structure prediction component of the ‘protein folding problem’ 8 —has been an important open research problem for more than 50 years 9 . Despite recent progress 10–14 , existing methods fall far short of atomic accuracy, especially when no homologous structure is available. Here we provide the first computational method that can regularly predict protein structures with atomic accuracy even in cases in which no similar structure is known. We validated an entirely redesigned version of our neural network-based model, AlphaFold, in the challenging 14th Critical Assessment of protein Structure Prediction (CASP14) 15 , demonstrating accuracy competitive with experimental structures in a majority of cases and greatly outperforming other methods. Underpinning the latest version of AlphaFold is a novel machine learning approach that incorporates physical and biological knowledge about protein structure, leveraging multi-sequence alignments, into the design of the deep learning algorithm.

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.

This paper is a broad and accessible survey of the methods we have at our disposal for Monte Carlo gradient estimation in machine learning and across the statistical sciences: the problem of computing the gradient of an expectation of a function with respect to parameters defining the distribution that is integrated; the problem of sensitivity analysis. In machine learning research, this gradient problem lies at the core of many learning problems, in supervised, unsupervised and reinforcement learning. We will generally seek to rewrite such gradients in a form that allows for Monte Carlo estimation, allowing them to be easily and efficiently used and analysed. We explore three strategies--the pathwise, score function, and measure-valued gradient estimators--exploring their historical development, derivation, and underlying assumptions. We describe their use in other fields, show how they are related and can be combined, and expand on their possible generalisations. Wherever Monte Carlo gradient estimators have been derived and deployed in the past, important advances have followed. A deeper and more widely-held understanding of this problem will lead to further advances, and it is these advances that we wish to support.

Tensor Train decomposition is used across many branches of machine learning. We present T3F -- a library for Tensor Train decomposition based on TensorFlow. T3F supports GPU execution, batch processing, automatic differentiation, and versatile functionality for the Riemannian optimization framework, which takes into account the underlying manifold structure to construct efficient optimization methods. The library makes it easier to implement machine learning papers that rely on the Tensor Train decomposition. T3F includes documentation, examples and 94% test coverage.

Computing the above gradient is difficult, since for many problems of interest the expectation is intractable and the high dimensionality of x makes estimating integrals numerically ineffective. This motivates the search for unbiased, low variance and computationally efficient Monte Carlo stochastic gradient estimators. Currently, the most commonly used unbiased estimators in machine learning are the score function (REINFORCE) [1, 2] and the pathwise (a.k.a. reparameterization) [3, 4, 5, 6] estimators. The pathwise estimator tends to have low variance, but requires the cost function to be differentiable and the distribution p(x;θ) to be reparametrizable, while the score function estimator is more widely applicable, but usually exhibits high variance. This motivates our search for a generally applicable estimator with low variance, and thus we will focus on a third class of estimators, the measure-valued derivatives.

We propose a single neural probabilistic model based on variational autoencoder that can be conditioned on an arbitrary subset of observed features and then sample the remaining features in "one shot". The features may be both real-valued and categorical. Training of the model is performed by stochastic variational Bayes. The experimental evaluation on synthetic data, as well as feature imputation and image inpainting problems, shows the effectiveness of the proposed approach and diversity of the generated samples.

Different approaches to generative modeling entail different approaches to evaluation. While some models admit test likelihood estimation, for others only proxy metrics for visual quality are being reported. In this paper, we propose a simple method to compute differential entropy of an arbitrary decoder-based generative model. Using this approach, we found that models with qualitatively different samples are distinguishable in terms of entropy. In particular, adversarially trained generative models typically have higher entropy than variational autoencoders. Additionally, we provide support for the application of entropy as a measure of sample diversity.

By providing a simple and efficient way of computing low-variance gradients of continuous random variables, the reparameterization trick has become the technique of choice for training a variety of latent variable models. However, it is not applicable to a number of important continuous distributions. We introduce an alternative approach to computing reparameterization gradients based on implicit differentiation and demonstrate its broader applicability by applying it to Gamma, Beta, Dirichlet, and von Mises distributions, which cannot be used with the classic reparameterization trick. Our experiments show that the proposed approach is faster and more accurate than the existing gradient estimators for these distributions.

We present a probabilistic model with discrete latent variables that control the computation time in deep learning models such as ResNets and LSTMs. A prior on the latent variables expresses the preference for faster computation. The amount of computation for an input is determined via amortized maximum a posteriori (MAP) inference. MAP inference is performed using a novel stochastic variational optimization method. The recently proposed adaptive computation time mechanism can be seen as an ad-hoc relaxation of this model. We demonstrate training using the general-purpose concrete relaxation of discrete variables. Evaluation on ResNet shows that our method matches the speed-accuracy trade-off of adaptive computation time, while allowing for evaluation with a simple deterministic procedure that has a lower memory footprint.

This paper proposes a deep learning architecture based on Residual Network that dynamically adjusts the number of executed layers for the regions of the image. This architecture is end-to-end trainable, deterministic and problem-agnostic. It is therefore applicable without any modifications to a wide range of computer vision problems such as image classification, object detection and image segmentation. We present experimental results showing that this model improves the computational efficiency of Residual Networks on the challenging ImageNet classification and COCO object detection datasets. Additionally, we evaluate the computation time maps on the visual saliency dataset cat2000 and find that they correlate surprisingly well with human eye fixation positions.

Variational inference is a powerful tool for approximate inference. However, it mainly focuses on the evidence lower bound as variational objective and the development of other measures for variational inference is a promising area of research. This paper proposes a robust modification of evidence and a lower bound for the evidence, which is applicable when the majority of the training set samples are random noise objects. We provide experiments for variational autoencoders to show advantage of the objective over the evidence lower bound on synthetic datasets obtained by adding uninformative noise objects to MNIST and OMNIGLOT. Additionally, for the original MNIST and OMNIGLOT datasets we observe a small improvement over the non-robust evidence lower bound.

This paper describes our solution of the Relevance Prediction Challenge. Our team ranked second in the contest. The goal of the contest is to predict relevance of URLs for search queries using search log. First we present the features we used. Our features are based on dierent assumptions about the properties of the dataset. Then we describe our machine learning technique. We trained multiple random forests on samples generated using the pair-wise approach. The resulting solution is a linear blend of the response vectors of the forests. The solution shows good performance and is likely not overt.