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Proteoform identification is an important problem in proteomics. The main task is to find a modified protein that best fits the input spectrum. To overcome the combinatorial explosion of possible proteoforms, the proteoform mass graph and spectrum mass graph are used to represent the protein database and the spectrum, respectively. The problem becomes finding an optimal alignment between the proteoform mass graph and the spectrum mass graph. Peak error correction is an important issue for computing an optimal alignment between the two input mass graphs.

We propose a faster algorithm for the error correction alignment of spectrum mass graph and proteoform mass graph problem and produce a program package TopMGFast. The newly designed algorithms require less space and running time so that we are able to compute global optimal alignments for the two input mass graphs in a reasonable time. For the local alignment version, experiments show that the running time of the new algorithm is reduced by 2.5 times. For the global alignment version, experiments show that the maximum mass errors between any pair of matched nodes in the alignments obtained by our method are within a small range as designed, while the alignments produced by the state-of-the-art method, TopMG, have very large maximum mass errors for many cases. The obtained alignment sizes are roughly the same for both TopMG and TopMGFast. Of course, TopMGFast needs more running time than TopMG. Therefore, our new algorithm can obtain more reliable global alignments within a reasonable time. This is the first time that global optimal error correction alignments can be obtained using real datasets.

The source code of the algorithm is available at https://github.com/Zeirdo/TopMGFast.

Model organisms are widely used to better understand the molecular causes of human disease. While sequence similarity greatly aids this cross-species transfer, sequence similarity does not imply functional similarity, and thus, several current approaches incorporate protein–protein interactions to help map findings between species. Existing transfer methods either formulate the alignment problem as a matching problem which pits network features against known orthology, or more recently, as a joint embedding problem.

We propose a novel state-of-the-art joint embedding solution: Embeddings to Network Alignment (ETNA). ETNA generates individual network embeddings based on network topological structure and then uses a Natural Language Processing-inspired cross-training approach to align the two embeddings using sequence-based orthologs. The final embedding preserves both within and between species gene functional relationships, and we demonstrate that it captures both pairwise and group functional relevance. In addition, ETNA’s embeddings can be used to transfer genetic interactions across species and identify phenotypic alignments, laying the groundwork for potential opportunities for drug repurposing and translational studies.

https://github.com/ylaboratory/ETNA

The state-of-art protein structure prediction methods such as AlphaFold are being widely used to predict structures of uncharacterized proteins in biomedical research. There is a significant need to further improve the quality and nativeness of the predicted structures to enhance their usability. In this work, we develop ATOMRefine, a deep learning-based, end-to-end, all-atom protein structural model refinement method. It uses a SE(3)-equivariant graph transformer network to directly refine protein atomic coordinates in a predicted tertiary structure represented as a molecular graph.

The method is first trained and tested on the structural models in AlphaFoldDB whose experimental structures are known, and then blindly tested on 69 CASP14 regular targets and 7 CASP14 refinement targets. ATOMRefine improves the quality of both backbone atoms and all-atom conformation of the initial structural models generated by AlphaFold. It also performs better than two state-of-the-art refinement methods in multiple evaluation metrics including an all-atom model quality score—the MolProbity score based on the analysis of all-atom contacts, bond length, atom clashes, torsion angles, and side-chain rotamers. As ATOMRefine can refine a protein structure quickly, it provides a viable, fast solution for improving protein geometry and fixing structural errors of predicted structures through direct coordinate refinement.

The source code of ATOMRefine is available in the GitHub repository (https://github.com/BioinfoMachineLearning/ATOMRefine). All the required data for training and testing are available at https://doi.org/10.5281/zenodo.6944368.

Gene network reconstruction from gene expression profiles is a compute- and data-intensive problem. Numerous methods based on diverse approaches including mutual information, random forests, Bayesian networks, correlation measures, as well as their transforms and filters such as data processing inequality, have been proposed. However, an effective gene network reconstruction method that performs well in all three aspects of computational efficiency, data size scalability, and output quality remains elusive. Simple techniques such as Pearson correlation are fast to compute but ignore indirect interactions, while more robust methods such as Bayesian networks are prohibitively time consuming to apply to tens of thousands of genes.

We developed maximum capacity path (MCP) score, a novel maximum-capacity-path-based metric to quantify the relative strengths of direct and indirect gene–gene interactions. We further present MCPNet, an efficient, parallelized gene network reconstruction software based on MCP score, to reverse engineer networks in unsupervised and ensemble manners. Using synthetic and real Saccharomyces cervisiae datasets as well as real Arabidopsis thaliana datasets, we demonstrate that MCPNet produces better quality networks as measured by AUPRC, is significantly faster than all other gene network reconstruction software, and also scales well to tens of thousands of genes and hundreds of CPU cores. Thus, MCPNet represents a new gene network reconstruction tool that simultaneously achieves quality, performance, and scalability requirements.

Source code freely available for download at https://doi.org/10.5281/zenodo.6499747 and https://github.com/AluruLab/MCPNet, implemented in C++ and supported on Linux.

Allostery enables changes to the dynamic behavior of a protein at distant positions induced by binding. Here, we present APOP, a new allosteric pocket prediction method, which perturbs the pockets formed in the structure by stiffening pairwise interactions in the elastic network across the pocket, to emulate ligand binding. Ranking the pockets based on the shifts in the global mode frequencies, as well as their mean local hydrophobicities, leads to high prediction success when tested on a dataset of allosteric proteins, composed of both monomers and multimeric assemblages.

Out of the 104 test cases, APOP predicts known allosteric pockets for 92 within the top 3 rank out of multiple pockets available in the protein. In addition, we demonstrate that APOP can also find new alternative allosteric pockets in proteins. Particularly interesting findings are the discovery of previously overlooked large pockets located in the centers of many protein biological assemblages; binding of ligands at these sites would likely be particularly effective in changing the protein’s global dynamics.

APOP is freely available as an open-source code (https://github.com/Ambuj-UF/APOP) and as a web server at https://apop.bb.iastate.edu/.

Gene annotation is the problem of mapping proteins to their functions represented as Gene Ontology (GO) terms, typically inferred based on the primary sequences. Gene annotation is a multi-label multi-class classification problem, which has generated growing interest for its uses in the characterization of millions of proteins with unknown functions. However, there is no standard GO dataset used for benchmarking the newly developed new machine learning models within the bioinformatics community. Thus, the significance of improvements for these models remains unclear.

The Gene Benchmarking database is the first effort to provide an easy-to-use and configurable hub for the learning and evaluation of gene annotation models. It provides easy access to pre-specified datasets and takes the non-trivial steps of preprocessing and filtering all data according to custom presets using a web interface. The GO bench web application can also be used to evaluate and display any trained model on leaderboards for annotation tasks.

The GO Benchmarking dataset is freely available at www.gobench.org. Code is hosted at github.com/mofradlab, with repositories for website code, core utilities and examples of usage (Supplementary Section S.7).

Supplementary data are available at Bioinformatics online.

Quality assessment (QA) of predicted protein tertiary structure models plays an important role in ranking and using them. With the recent development of deep learning end-to-end protein structure prediction techniques for generating highly confident tertiary structures for most proteins, it is important to explore corresponding QA strategies to evaluate and select the structural models predicted by them since these models have better quality and different properties than the models predicted by traditional tertiary structure prediction methods.

We develop EnQA, a novel graph-based 3D-equivariant neural network method that is equivariant to rotation and translation of 3D objects to estimate the accuracy of protein structural models by leveraging the structural features acquired from the state-of-the-art tertiary structure prediction method—AlphaFold2. We train and test the method on both traditional model datasets (e.g. the datasets of the Critical Assessment of Techniques for Protein Structure Prediction) and a new dataset of high-quality structural models predicted only by AlphaFold2 for the proteins whose experimental structures were released recently. Our approach achieves state-of-the-art performance on protein structural models predicted by both traditional protein structure prediction methods and the latest end-to-end deep learning method—AlphaFold2. It performs even better than the model QA scores provided by AlphaFold2 itself. The results illustrate that the 3D-equivariant graph neural network is a promising approach to the evaluation of protein structural models. Integrating AlphaFold2 features with other complementary sequence and structural features is important for improving protein model QA.

The source code is available at https://github.com/BioinfoMachineLearning/EnQA.

Supplementary data are available at Bioinformatics online.

metal-binding proteins have a central role in maintaining life processes. Nearly one-third of known protein structures contain metal ions that are used for a variety of needs, such as catalysis, DNA/RNA binding, protein structure stability, etc. Identifying metal-binding proteins is thus crucial for understanding the mechanisms of cellular activity. However, experimental annotation of protein metal-binding potential is severely lacking, while computational techniques are often imprecise and of limited applicability.

we developed a novel machine learning-based method, mebipred, for identifying metal-binding proteins from sequence-derived features. This method is over 80% accurate in recognizing proteins that bind metal ion-containing ligands; the specific identity of 11 ubiquitously present metal ions can also be annotated. mebipred is reference-free, i.e. no sequence alignments are involved, and is thus faster than alignment-based methods; it is also more accurate than other sequence-based prediction methods. Additionally, mebipred can identify protein metal-binding capabilities from short sequence stretches, e.g. translated sequencing reads, and, thus, may be useful for the annotation of metal requirements of metagenomic samples. We performed an analysis of available microbiome data and found that ocean, hot spring sediments and soil microbiomes use a more diverse set of metals than human host-related ones. For human microbiomes, physiological conditions explain the observed metal preferences. Similarly, subtle changes in ocean sample ion concentration affect the abundance of relevant metal-binding proteins. These results highlight mebipred’s utility in analyzing microbiome metal requirements.

mebipred is available as a web server at services.bromberglab.org/mebipred and as a standalone package at https://pypi.org/project/mymetal/.

Supplementary data are available at Bioinformatics online.

Mapping positional features from one-dimensional (1D) sequences onto three-dimensional (3D) structures of biological macromolecules is a powerful tool to show geometric patterns of biochemical annotations and provide a better understanding of the mechanisms underpinning protein and nucleic acid function at the atomic level.

We present a new library designed to display fully customizable interactive views between 1D positional features of protein and/or nucleic acid sequences and their 3D structures as isolated chains or components of macromolecular assemblies.

https://github.com/rcsb/rcsb-saguaro-3d.

Supplementary data are available at Bioinformatics online.

A new dynamic community identifier (DCI) is presented that relies upon protein residue dynamic cross-correlations generated by Gaussian elastic network models to identify those residue clusters exhibiting motions within a protein. A number of examples of communities are shown for diverse proteins, including GPCRs. It is a tool that can immediately simplify and clarify the most essential functional moving parts of any given protein. Proteins usually can be subdivided into groups of residues that move as communities. These are usually densely packed local sub-structures, but in some cases can be physically distant residues identified to be within the same community. The set of these communities for each protein are the moving parts. The ways in which these are organized overall can aid in understanding many aspects of functional dynamics and allostery. DCI enables a more direct understanding of functions including enzyme activity, action across membranes and changes in the community structure from mutations or ligand binding. The DCI server is freely available on a web site (https://dci.bb.iastate.edu/).

Supplementary data are available at Bioinformatics online.