Binding of peptides to MHC class I (MHC-I) molecules is the most selective event in the processing and presentation of antigens to cytotoxic T lymphocytes (CTL) and insights into the mechanisms that govern peptide-MHC-I binding should facilitate our understanding of CTL biology. Peptide-MHC-I interactions have traditionally been quantified by the strength of the interaction, i.e. the binding affinity, yet it has been show that the stability of the peptide-MHC-I complex is a better correlate of immunogenicity compared to binding affinity. Here, we have experimentally analyzed peptide-MHC-I complex stability of a large panel of human MHC-I allotypes and generated a body of data sufficient to develop neural networks based pan-specific predictor of peptide-MHC-I complex stability. Integrating the neural networks predictors of peptide-MHC-I complex stability with state-of-the-art predictors of peptide-MHC-I binding is shown to significantly improve the prediction of CTL epitopes. The method is publicly available at www.cbs.dtu.dk/services/NetMHCstabpan.
Motivation In contrast to messenger RNAs, the function of the wide range of existing long noncoding RNAs (lncRNAs) largely depends on their structure, which determines interactions with partner molecules. Thus, the determination or prediction of the secondary structure of lncRNAs is critical to uncover their function. Classical approaches for predicting RNA secondary structure have been based on dynamic programming and thermodynamic calculations. In the last 4 years, a growing number of machine learning (ML)-based models, including deep learning (DL), have achieved breakthrough performance in structure prediction of biomolecules such as proteins and have outperformed classical methods in short transcripts folding. Nevertheless, the accurate prediction for lncRNA still remains far from being effectively solved. Notably, the myriad of new proposals has not been systematically and experimentally evaluated. Results In this work, we compare the performance of the classical methods as well as the most recently proposed approaches for secondary structure prediction of RNA sequences using a unified and consistent experimental setup. We use the publicly available structural profiles for 3023 yeast RNA sequences, and a novel benchmark of well-characterized lncRNA structures from different species. Moreover, we propose a novel metric to assess the predictive performance of methods, exclusively based on the chemical probing data commonly used for profiling RNA structures, avoiding any potential bias incorporated by computational predictions when using dot-bracket references. Our results provide a comprehensive comparative assessment of existing methodologies, and a novel and public benchmark resource to aid in the development and comparison of future approaches. Availability Full source code and benchmark datasets are available at: https://github.com/sinc-lab/lncRNA-folding Contact lbugnon@sinc.unl.edu.ar
Supplementary data are available at Bioinformatics online.
A representation method is an algorithm that calculates numerical feature vectors for samples in a dataset. Such vectors, also known as embeddings, define a relatively low-dimensional space able to efficiently encode high-dimensional data. Very recently, many types of learned data representations based on machine learning have appeared and are being applied to several tasks in bioinformatics. In particular, protein representation learning methods integrate different types of protein information (sequence, domains, etc.), in supervised or unsupervised learning approaches, and provide embeddings of protein sequences that can be used for downstream tasks. One task that is of special interest is the automatic function prediction of the huge number of novel proteins that are being discovered nowadays and are still totally uncharacterized. However, despite its importance, up to date there is not a fair benchmark study of the predictive performance of existing proposals on the same large set of proteins and for very concrete and common bioinformatics tasks. Therefore, this lack of benchmark studies prevent the community from using adequate predictive methods for accelerating the functional characterization of proteins. In this study, we performed a detailed comparison of protein sequence representation learning methods, explaining each approach and comparing them with an experimental benchmark on several bioinformatics tasks: (i) determining protein sequence similarity in the embedding space; (ii) inferring protein domains and (iii) predicting ontology-based protein functions. We examine the advantages and disadvantages of each representation approach over the benchmark results. We hope the results and the discussion of this study can help the community to select the most adequate machine learning-based technique for protein representation according to the bioinformatics task at hand.
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