Inverse protein folding is challenging due to its inherent one-to-many mapping characteristic, where numerous possible amino acid sequences can fold into a single, identical protein backbone. This task involves not only identifying viable sequences but also representing the sheer diversity of potential solutions. However, existing discriminative models, such as transformer-based auto-regressive models, struggle to encapsulate the diverse range of plausible solutions. In contrast, diffusion probabilistic models, as an emerging genre of generative approaches, offer the potential to generate a diverse set of sequence candidates for determined protein backbones. We propose a novel graph denoising diffusion model for inverse protein folding, where a given protein backbone guides the diffusion process on the corresponding amino acid residue types. The model infers the joint distribution of amino acids conditioned on the nodes' physiochemical properties and local environment. Moreover, we utilize amino acid replacement matrices for the diffusion forward process, encoding the biologically meaningful prior knowledge of amino acids from their spatial and sequential neighbors as well as themselves, which reduces the sampling space of the generative process. Our model achieves state-of-the-art performance over a set of popular baseline methods in sequence recovery and exhibits great potential in generating diverse protein sequences for a determined protein backbone structure.

A.1 Access instructions OpenProteinSet is hosted by the Registry of Open Data on AWS (RODA) and can be accessed at the following link: registry.opendata.aws/openfold/. A.2 Documentation and intended uses We include a datasheet [1] in Section B. Detailed documentation on the precise structure and content of the dataset is provided on the dataset's landing page. A.3 Data format All OpenProteinSet files are in standard plaintext formats (A3M for MSAs, HHSearch format for template hits, and PDB for structure files) that can be read by a wide variety of bioinformatics software. A.5 License OpenProteinSet is made available under the CCBY 4.0 license. A copy of the license is provided with the dataset.

Multiple sequence alignments (MSAs) of proteins encode rich biological information and have been workhorses in bioinformatic methods for tasks like protein design and protein structure prediction for decades. Recent breakthroughs like AlphaFold2 that use transformers to attend directly over large quantities of raw MSAs have reaffirmed their importance. Generation of MSAs is highly computationally intensive, however, and no datasets comparable to those used to train AlphaFold2 have been made available to the research community, hindering progress in machine learning for proteins. To remedy this problem, we introduce OpenProteinSet, an open-source corpus of more than 16 million MSAs, associated structural homologs from the Protein Data Bank, and AlphaFold2 protein structure predictions. We have previously demonstrated the utility of OpenProteinSet by successfully retraining AlphaFold2 on it. We expect OpenProteinSet to be broadly useful as training and validation data for 1) diverse tasks focused on protein structure, function, and design and 2) large-scale multimodal machine learning research.

Proteins are responsible for most of the functions in life, and thus are the central focus of many areas of biomedicine. Protein structure is strongly related to protein function, but is difficult to elucidate experimentally, therefore computational structure prediction is a crucial task on the way to solve many biological questions. A contact map is a compact representation of the three-dimensional structure of a protein via the pairwise contacts between the amino acids constituting the protein. We use a convolutional network to calculate protein contact maps from detailed evolutionary coupling statistics between positions in the protein sequence. The input to the network has an image-like structure amenable to convolutions, but every "pixel" instead of color channels contains a bipartite undirected edge-weighted graph. We propose several methods for treating such "graph-valued images" in a convolutional network. The proposed method outperforms state-of-the-art methods by a considerable margin.

We explore optimally training protein language models, an area of significant interest in biological research where guidance on best practices is limited.Most models are trained with extensive compute resources until performance gains plateau, focusing primarily on increasing model sizes rather than optimizing the efficient compute frontier that balances performance and compute budgets.Our investigation is grounded in a massive dataset consisting of 939 million protein sequences. We trained over 300 models ranging from 3.5 million to 10.7 billion parameters on 5 to 200 billion unique tokens, to investigate the relations between model sizes, training token numbers, and objectives.First, we observed the effect of diminishing returns for the Causal Language Model (CLM) and that of overfitting for Masked Language Model (MLM) when repeating the commonly used Uniref database. To address this, we included metagenomic protein sequences in the training set to increase the diversity and avoid the plateau or overfitting effects. Second, we obtained the scaling laws of CLM and MLM on Transformer, tailored to the specific characteristics of protein sequence data. Third, we observe a transfer scaling phenomenon from CLM to MLM, further demonstrating the effectiveness of transfer through scaling behaviors based on estimated Effectively Transferred Tokens.Finally, to validate our scaling laws, we compare the large-scale versions of ESM-2 and PROGEN2 on downstream tasks, encompassing evaluations of protein generation as well as structure-and function-related tasks, all within less or equivalent pre-training compute budgets.

Inverse protein folding is a fundamental task in computational protein design, which aims to design protein sequences that fold into the desired backbone structures. While the development of machine learning algorithms for this task has seen significant success, the prevailing approaches, which predominantly employ a discriminative formulation, frequently encounter the error accumulation issue and often fail to capture the extensive variety of plausible sequences. To fill these gaps, we propose Bridge-IF, a generative diffusion bridge model for inverse folding, which is designed to learn the probabilistic dependency between the distributions of backbone structures and protein sequences. Specifically, we harness an expressive structure encoder to propose a discrete, informative prior derived from structures, and establish a Markov bridge to connect this prior with native sequences.

Generative protein language models are a natural way to design new proteins with desired functions.