The accurate “base pairing” in RNA molecules, which leads to the prediction of RNA secondary structures, is crucial in order to explain unknown biological operations. Recently, COVID-19, a widespread disease, has caused many deaths, affecting humanity in an unprecedented way. SARS-CoV-2, a single-stranded RNA virus, has shown the significance of analyzing these molecules and their structures. This paper aims to create a pioneering framework in the direction of predicting specific RNA structures, leveraging syntactic pattern recognition. The proposed framework, Knotify+, addresses the problem of predicting H-type pseudoknots, including bulges and internal loops, by featuring the power of context-free grammar (CFG). We combine the grammar’s advantages with maximum base pairing and minimum free energy to tackle this ambiguous task in a performant way. Specifically, our proposed methodology, Knotify+, outperforms state-of-the-art frameworks with regards to its accuracy in core stems prediction. Additionally, it performs more accurately in small sequences and presents a comparable accuracy rate in larger ones, while it requires a smaller execution time compared to well-known platforms. The Knotify+ source code and implementation details are available as a public repository on GitHub.

Obtaining valuable clues for noncoding RNA (ribonucleic acid) subsequences remains a significant challenge, acknowledging that most of the human genome transcribes into noncoding RNA parts related to unknown biological operations. Capturing these clues relies on accurate “base pairing” prediction, also known as “RNA secondary structure prediction”. As COVID-19 is considered a severe global threat, the single-stranded SARS-CoV-2 virus reveals the importance of establishing an efficient RNA analysis toolkit. This work aimed to contribute to that by introducing a novel system committed to predicting RNA secondary structure patterns (i.e., RNA’s pseudoknots) that leverage syntactic pattern-recognition strategies. Having focused on the pseudoknot predictions, we formalized the secondary structure prediction of the RNA to be primarily a parsing and, secondly, an optimization problem. The proposed methodology addresses the problem of predicting pseudoknots of the first order (H-type). We introduce a context-free grammar (CFG) that affords enough expression power to recognize potential pseudoknot pattern. In addition, an alternative methodology of detecting possible pseudoknots is also implemented as well, using a brute-force algorithm. Any input sequence may highlight multiple potential folding patterns requiring a strict methodology to determine the single biologically realistic one. We conscripted a novel heuristic over the widely accepted notion of free-energy minimization to tackle such ambiguity in a performant way by utilizing each pattern’s context to unveil the most prominent pseudoknot pattern. The overall process features polynomial-time complexity, while its parallel implementation enhances the end performance, as proportional to the deployed hardware. The proposed methodology does succeed in predicting the core stems of any RNA pseudoknot of the test dataset by performing a 76.4% recall ratio. The methodology achieved a F1-score equal to 0.774 and MCC equal 0.543 in discovering all the stems of an RNA sequence, outperforming the particular task. Measurements were taken using a dataset of 262 RNA sequences establishing a performance speed of 1.31, 3.45, and 7.76 compared to three well-known platforms. The implementation source code is publicly available under knotify github repo.

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The observation and analysis of RNA molecules have proved crucial for the understanding of various processes in nature. Scientists have mined knowledge and drawn conclusions using experimental methods for decades. Leveraging advanced computational methods in recent years has led to fast and more accurate results in all areas of interest. One highly challenging task, in terms of RNA analysis, is the prediction of its structure, which provides valuable information about how it transforms and operates numerous significant tasks in organisms. In this paper, we focus on the prediction of the 2-D or secondary structure of RNA, specifically, on a rare but yet complex type of pseudoknot, the L-type pseudoknot, extending our previous framework specialized for H-type pseudoknots. We propose a grammar-based framework that predicts all possible L-type pseudoknots of a sequence in a reasonable response time, leveraging also the advantages of core biological principles, such as maximum base pairs and minimum free energy. In order to evaluate the effectiveness of our methodology, we assessed four performance metrics: precision; recall; Matthews correlation coefficient (MCC); and F1-score, which is the harmonic mean of precision and recall. Our methodology outperformed the other three well known methods in terms of Precision, with a score of 0.844, while other methodologies scored 0.500, 0.333, and 0.308. Regarding the F1-score, our platform scored 0.671, while other methodologies scored 0.661, 0.449, and 0.449. The proposed methodology surpassed all methods in terms of the MCC metric, achieving a score of 0.521. The proposed method was added to our RNA toolset, which aims to enhance the capabilities of biologists in the prediction of RNA motifs, including pseudoknots, and holds the potential to be applied in a multitude of biological domains, including gene therapy, drug design, and comprehending RNA functionality. Furthermore, the suggested approach can be employed in conjunction with other methodologies to enhance the precision of RNA structure prediction.

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