Search

Graph Neural Networks have proven to be very valuable models for the solution of a wide variety of problems on molecular graphs, as well as in many other research fields involving graph-structured data. Molecules are heterogeneous graphs composed of atoms of different species. Composite graph neural networks process heterogeneous graphs with multiple-state-updating networks, each one dedicated to a particular node type. This approach allows for the extraction of information from s graph more efficiently than standard graph neural networks that distinguish node types through a one-hot encoded type of vector. We carried out extensive experimentation on eight molecular graph datasets and on a large number of both classification and regression tasks. The results we obtained clearly show that composite graph neural networks are far more efficient in this setting than standard graph neural networks. [ABSTRACT FROM AUTHOR]

Escherichia coli is a benchmark organism, which has been deeply studied by the scientific community for decades, obtaining a vast amount of metabolic and genetic data. Among these data, estimates of the translation speed of ribosomes over their genome are available. These estimates are based on Ribo-Seq profiles, where the abundance of a particular fragment of mRNA in a profile indicates that it was sampled many times inside a cell. Various measurements of Ribo-Seq profiles are available for Escherichia coli, yet they do not always show a high degree of correspondence, which means that they can vary significantly in different experimental setups, being characterized by poor reproducibility. Indeed, within Ribo-Seq profiles, the translation speed for some sequences is easier to estimate, while for others, an uneven distribution of consensus among the different estimates is evidenced. Our goal is to develop an artificial intelligence method that can be trained on a small pool of highly reproducible sequences to establish their translation rate, which can then be exploited to calculate a more reliable estimate of the translation speed on the rest of the genome. [ABSTRACT FROM AUTHOR]

[Display omitted] • A sequential algorithm for the generation of molecular graphs is presented. • Graph Neural Networks exploit all the information available at each step. • The sequential and modular nature of our method makes it interpretable. • Each module is trained independently, simplifying learning and optimization. • The model is evaluated on the QM9 and Zinc benchmark datasets of molecules. Drug Discovery is a fundamental and ever-evolving field of research. The design of new candidate molecules requires large amounts of time and money, and computational methods are being increasingly employed to cut these costs. Machine learning methods are ideal for the design of large amounts of potential new candidate molecules, which are naturally represented as graphs. Graph generation is being revolutionized by deep learning methods, and molecular generation is one of its most promising applications. In this paper, we introduce a sequential molecular graph generator based on a set of graph neural network modules, which we call MG2N2. At each step, a node or a group of nodes is added to the graph, along with its connections. The modular architecture simplifies the training procedure, also allowing an independent retraining of a single module. Sequentiality and modularity make the generation process interpretable. The use of Graph Neural Networks maximizes the information in input at each generative step, which consists of the subgraph produced during the previous steps. Experiments of unconditional generation on the QM9 and Zinc datasets show that our model is capable of generalizing molecular patterns seen during the training phase, without overfitting. The results indicate that our method is competitive, and outperforms challenging baselines for unconditional generation. [ABSTRACT FROM AUTHOR]

Understanding the molecular mechanisms that correlate pathologies with missense mutations is of critical importance for disease risk estimations and for devising personalized therapies. Thus, we have performed a bioinformatic survey of ClinVar, a database of human genomic variations, to find signals that can account for missense mutation pathogenicity. Arginine resulted as the most frequently replaced amino acid both in benign and pathogenic mutations. By adding the structural dimension to this investigation to increase its resolution, we found that arginine mutations occurring at the protein–DNA interface increase pathogenicity 6.5 times with respect to benign variants. Glycine is the second amino acid among all the pathological missense mutations. Necessarily replaced by larger amino acids, glycine substitutions perturb the structural stability of proteins and, therefore, their functions, being mostly located in buried protein moieties. Arginine and glycine appear as representative of missense mutations causing respective changes in interaction processes and protein structural features, the two main molecular mechanisms of genome-induced pathologies. [ABSTRACT FROM AUTHOR]

The recent release of COVID-19 spike glycoprotein allows detailed analysis of the structural features that are required for stabilizing the infective form of its quaternary assembly. Trying to disassemble the trimeric structure of COVID-19 spike glycoprotein, we analyzed single protomer surfaces searching for concave moieties that are located at the three protomer-protomer interfaces. The presence of some druggable pockets at these interfaces suggested that some of the available drugs in Drug Bank could destabilize the quaternary spike glycoprotein formation by binding to these pockets, therefore interfering with COVID-19 life cycle. The approach we propose here can be an additional strategy to fight against the deadly virus. Ligands of COVID-19 spike glycoprotein that we have predicted in the present computational investigation, might be the basis for new experimental studies in vitro and in vivo. Image 1 • Search for ligand binding sites in COVID-19 S glycoprotein protomeric interfaces. • Structure based ligand selection for interfering to COVID-19 S glycoprotein assembly. • Ligand-protomer docking simulation to find the best candidates for therapeutic use. [ABSTRACT FROM AUTHOR]

Nowadays, it is well established that most of the human diseases which are not related to pathogen infections have their origin from DNA disorders. Thus, DNA mutations, waiting for the availability of CRISPR-like remedies, will propagate into proteomics, offering the possibility to select natural or synthetic molecules to fight against the effects of malfunctioning proteins. Drug discovery, indeed, is a flourishing field of biotechnological research to improve human health, even though the development of a new drug is increasingly more expensive in spite of the massive use of informatics in Medicinal Chemistry. CRISPR technology adds new alternatives to cure diseases by removing DNA defects responsible of genome-related pathologies. In principle, the same technology, however, could also be exploited to induce protein mutations whose effects are controlled by the presence of suitable ligands. In this paper, a new idea is proposed for the realization of mutated proteins, on the surface of which more spacious transient pockets are formed and, therefore, are more suitable for hosting drugs. In particular, new allosteric sites are obtained by replacing amino-acids with bulky side chains with glycine, Gly, the smallest natural amino-acid. We also present a machine learning approach to evaluate the druggability score of new (or enlarged) pockets. Preliminary experimental results are very promising, showing that 10% of the sites created by the Gly-pipe software are druggable. [ABSTRACT FROM AUTHOR]

Drug side effects (DSEs), or adverse drug reactions (ADRs), constitute an important health risk, given the approximately 197,000 annual DSE deaths in Europe alone. Therefore, during the drug development process, DSE detection is of utmost importance, and the occurrence of ADRs prevents many candidate molecules from going through clinical trials. Thus, early prediction of DSEs has the potential to massively reduce drug development times and costs. In this work, data are represented in a non-euclidean manner, in the form of a graph-of-graphs domain. In such a domain, structures of molecule are represented by molecular graphs, each of which becomes a node in the higher-level graph. In the latter, nodes stand for drugs and genes, and arcs represent their relationships. This relational nature represents an important novelty for the DSE prediction task, and it is directly used during the prediction. For this purpose, the MolecularGNN model is proposed. This new classifier is based on graph neural networks, a connectionist model capable of processing data in the form of graphs. The approach represents an improvement over a previous method, called DruGNN, as it is also capable of extracting information from the graph-based molecular structures, producing a task-based neural fingerprint (NF) of the molecule which is adapted to the specific task. The architecture has been compared with other GNN models in terms of performance, showing that the proposed approach is very promising. [ABSTRACT FROM AUTHOR]

Protein–protein interactions (PPIs) are fundamental processes governing cellular functions, crucial for understanding biological systems at the molecular level. Compared to experimental methods for PPI prediction and site identification, computational deep learning approaches represent an affordable and efficient solution to tackle these problems. Since protein structure can be summarized as a graph, graph neural networks (GNNs) represent the ideal deep learning architecture for the task. In this work, PPI prediction is modeled as a node-focused binary classification task using a GNN to determine whether a generic residue is part of the interface. Biological data were obtained from the Protein Data Bank in Europe (PDBe), leveraging the Protein Interfaces, Surfaces, and Assemblies (PISA) service. To gain a deeper understanding of how proteins interact, the data obtained from PISA were assembled into three datasets: Whole, Interface, and Chain, consisting of data on the whole protein, couples of interacting chains, and single chains, respectively. These three datasets correspond to three different nuances of the problem: identifying interfaces between protein complexes, between chains of the same protein, and interface regions in general. The results indicate that GNNs are capable of solving each of the three tasks with very good performance levels. [ABSTRACT FROM AUTHOR]

In recent years, the Ribosome profiling technique (Ribo–seq) has emerged as a powerful method for globally monitoring the translation process in vivo at single nucleotide resolution. Based on deep sequencing of mRNA fragments, Ribo–seq allows to obtain profiles that reflect the time spent by ribosomes in translating each part of an open reading frame. Unfortunately, the profiles produced by this method can vary significantly in different experimental setups, being characterized by a poor reproducibility. To address this problem, we have employed a statistical method for the identification of highly reproducible Ribo–seq profiles, which was tested on a set of E. coli genes. State-of-the-art artificial neural network models have been used to validate the quality of the produced sequences. Moreover, new insights into the dynamics of ribosome translation have been provided through a statistical analysis on the obtained sequences. [ABSTRACT FROM AUTHOR]

The increasing digitization and datification of all aspects of people's daily life, and the consequent growth in the use of personal data, are increasingly challenging the current development and adoption of Machine Learning (ML). First, the sheer complexity and amount of data available in these applications strongly demands for ML algorithms that can be trained directly on complex structures, which can be naturally described by graphs. In fact, graphs inherently capture information about entities, their attributes, and relationships between them. Directly applying ML to graphs relieves domain experts and data scientists from the challenging and time-consuming problem of designing a suitable vector-based data representation used by classical ML techniques. Second, ML algorithms should not only be designed to achieve high technical and functional standards; as the automated decisions provided by these algorithms can have a relevant impact on people's lives, their behavior has to be aligned with the values and principles of individuals and society. This demands for designing automated algorithms that we, as humans, can trust, fulfilling the requirements of fairness, robustness, privacy, and explainability. Third, designing effective ML algorithms requires skills and expertise developed at different levels. This substantially hinders the democratization and widespread availability of such technology for society at large, which in turn demands for improving the level of automatization and systematization of their design process, while also providing guarantees on their performance. For this reason, this paper provides an overview of the current works focused towards learning trustworthily, automatically, and with guarantees on graphs. [ABSTRACT FROM AUTHOR]