Computational Methods Research Articles

State-of-the-RNArt: benchmarking current methods for RNA 3D structure prediction.

RNAs are essential molecules involved in numerous biological functions. Understanding RNA functions requires the knowledge of their 3D structures. Computational methods have been developed for over two decades to predict the 3D conformations from RNA sequences. These computational methods have been widely used and are usually categorised as either ab initio or template-based. The performances remain to be improved. Recently, the rise of deep learning has changed the sight of novel approaches. Deep learning methods are promising, but their adaptation to RNA 3D structure prediction remains difficult. In this paper, we give a brief review of the ab initio, template-based and novel deep learning approaches. We highlight the different available tools and provide a benchmark on nine methods using the RNA-Puzzles dataset. We provide an online dashboard that shows the predictions made by benchmarked methods, freely available on the EvryRNA platform: https://evryrna.ibisc.univ-evry.fr/evryrna/state_of_the_rnart/.

The Power of Molecular Dynamics Simulations and Their Applications to Discover Cysteine Protease Inhibitors.

A large family of enzymes with the function of hydrolyzing peptide bonds, called peptidases or cysteine proteases (CPs), are divided into three categories according to the peptide chain involved. CPs catalyze the hydrolysis of amide, ester, thiol ester, and thioester peptide bonds. They can be divided into several groups, such as papain-like (CA), viral chymotrypsin-like CPs (CB), papain-like endopeptidases of RNA viruses (CC), legumain-type caspases (CD), and showing active residues of His, Glu/Asp, Gln, Cys (CE). The catalytic mechanism of CPs is the essential cysteine residue present in the active site. These mechanisms are often studied through computational methods that provide new information about the catalytic mechanism and identify inhibitors. The role of computational methods during drug design and development stages is increasing. Methods in Computer-Aided Drug Design (CADD) accelerate the discovery process, increase the chances of selecting more promising molecules for experimental studies, and can identify critical mechanisms involved in the pathophysiology and molecular pathways of action. Molecular dynamics (MD) simulations are essential in any drug discovery program due to their high capacity for simulating a physiological environment capable of unveiling significant inhibition mechanisms of new compounds against target proteins, especially CPs. Here, a brief approach will be shown on MD simulations and how the studies were applied to identify inhibitors or critical information against cysteine protease from several microorganisms, such as Trypanosoma cruzi (cruzain), Trypanosoma brucei (rhodesain), Plasmodium spp. (falcipain), and SARS-CoV-2 (Mpro). We hope the readers will gain new insights and use our study as a guide for potential compound identifications using MD simulations.

Identification of potential human targets of glyphosate using in silico target fishing

Glyphosate is a widely used herbicide known for its effectiveness in weed control; and it is an inhibitor of the plant enzyme 5-enolpyruvylshikimate-3-phosphate synthase. Currently, it is one of the most extensively used non-specific herbicides in agroindustry. However, toxic effects of glyphosate have recently been reported, including endocrine disruption, metabolic alterations, teratogenic, tumorigenic, and hepatorenal effects. Additionally, there are environmental concerns related to possible interactions with proteins from microorganisms, aquatic organisms, and mammals.Research on the description of these interactions has gained interest, primarily with the aim of generating recommendations in terms of its use and possible regulations. On the other hand, computational methods have emerged to identify potential targets or unintended targets among numerous possible receptors. Several programs, online services, and databases are available for use in these methods.In this study, we employed a set of online tools for computational target fishing to identify receptors of glyphosate. A set of thirteen targets were selected using six fishing tools. Furthermore, docking procedures were performed to investigate the expected interactions and binding energies. Certain associations with diseases are also reported.

In Silico Design and Evaluation of a Novel Therapeutic Agent Against the Spike Protein as a Novel Treatment Strategy for COVID-19 Treatment.

Coronavirus disease 2019 (COVID-19) is a viral respiratory disease that is associated with severe damage to other human organs. It causes by a novel coronavirus, and it is spreading all over the world. To date, there is some approved vaccine or therapeutic agent which could be effective against this disease. But their effectiveness against mutated strains is not studied completely. The spike glycoprotein on the surface of the coronaviruses gives the virus the ability to bind to host cell receptors and enter cells. Inhibition of attachment of these spikes can lead to virus neutralization by inhibiting viral entrance. In this study, we tried to use the virus entrance strategy against itself by utilizing virus receptor (ACE-2) in order to design an engineered protein consisting of a human Fc antibody fragment and a part of ACE-2, which reacts with virus RBD, and we also evaluated this interaction by computational methods and in silico methods. Subsequently, we have designed a new protein structure to bind with this site and inhibit the virus from attaching to its cell receptor, mechanically or chemically. Various in silico software, bioinformatics, and patent databases were used to retrieve the requested gene and protein sequences. The physicochemical properties and possibility of allergenicity were also examined. Three-dimensional structure prediction and molecular docking were also performed to develop the most suitable therapeutic protein. The designed protein consisted of a total of 256 amino acids with a molecular weight of 28984.62 and 5.92 as a theoretical isoelectric point. Instability and aliphatic index and grand average of hydropathicity are 49.99, 69.57 and -0.594, respectively. In silico studies can provide a good opportunity to study viral proteins and new drugs or compounds since they do not need direct exposure to infectious agents or equipped laboratories. The suggested therapeutic agent should be further characterized in vitro and in vivo.

Computational protein design - where it goes?

Proteins have been playing a critical role in the regulation of diverse biological processes related to human life. With the increasing demand, functional proteins are sparse in this immense sequence space. Therefore, protein design has become an important task in various fields, including medicine, food, energy, materials, etc. Directed evolution has recently led to significant achievements. Molecular modification of proteins through directed evolution technology has significantly advanced the fields of enzyme engineering, metabolic engineering, medicine, and beyond. However, it is impossible to identify desirable sequences from a large number of synthetic sequences alone. As a result, computational methods, including data-driven machine learning and physics-based molecular modeling, have been introduced to protein engineering to produce more functional proteins. This review focuses on recent advances in computational protein design, highlighting the applicability of different approaches as well as their limitations.

Bi-directional DC-AC using BLDC motor for electric and hybrid electric vehicles applications with reduced number of switches

Electric scooters often have a single design and are difficult to produce at a greater level than other forms of transportation. A possible cut electric scooter is built with the optimization design of the vehicle combustible wealth and the pollution characteristics in order to arrange to a correct solution by resolving each and every challenge. The engines' electrical systems are comprised of lead acid batteries. For the sake of a straightforward simulation procedure, the engine operates in two states ON and OFF while the vehicle's speed is regulated in three ranges roughly corresponding to high, medium, and low. The planetary speed ratio and the final drive speed ratio are gathered in the computation method's general outline. Utilizing simulation MATLAB, the findings of optimization strategies are resolved. This technique improves the fuel plenty and discharge quality of the possibility cut electric automobiles.

Use of analytical hierarchy process for selecting and prioritizing islanding detection methods in power grids

One of the problems that are associated to power systems is islanding condition, which must be rapidly and properly detected to prevent any negative consequences on the system's protection, stability, and security. This paper offers a thorough overview of several islanding detection strategies, which are divided into two categories: classic approaches, including local and remote approaches, and modern techniques, including techniques based on signal processing and computational intelligence. Additionally, each approach is compared and assessed based on several factors, including implementation costs, non-detected zones, declining power quality, and response times using the analytical hierarchy process (AHP). The multi-criteria decision-making analysis shows that the overall weight of passive methods (24.7%), active methods (7.8%), hybrid methods (5.6%), remote methods (14.5%), signal processing-based methods (26.6%), and computational intelligent-based methods (20.8%) based on the comparison of all criteria together. Thus, it can be seen from the total weight that hybrid approaches are the least suitable to be chosen, while signal processing-based methods are the most appropriate islanding detection method to be selected and implemented in power system with respect to the aforementioned factors. Using Expert Choice software, the proposed hierarchy model is studied and examined.

ChimericFragments: computation, analysisand visualization of global RNA networks.

RNA-RNA interactions are a key feature of post-transcriptional gene regulation in all domains of life. While ever more experimental protocols are being developed to study RNA duplex formation on a genome-wide scale, computational methods for the analysis and interpretation of the underlying data are lagging behind. Here, we present ChimericFragments, an analysis framework for RNA-seq experiments that produce chimeric RNA molecules. ChimericFragments implements a novel statistical method based on the complementarity of the base-pairing RNAs around their ligation site and provides an interactive graph-based visualization for data exploration and interpretation. ChimericFragments detects true RNA-RNA interactions with high precision and is compatible with several widely used experimental procedures such as RIL-seq, LIGR-seqor CLASH. We further demonstrate that ChimericFragments enables the systematic detection of novel RNA regulators and RNA-target pairs with crucial roles in microbial physiology and virulence. ChimericFragments is written in Julia and available at: https://github.com/maltesie/ChimericFragments.

Engineering G protein-coupled receptors for stabilization.

G protein-coupled receptors (GPCRs) are one of the most important families of targets for drug discovery. One of the limiting steps in the study of GPCRs has been their stability, with significant and time-consuming protein engineering often used to stabilize GPCRs for structural characterization and drug screening. Unfortunately, computational methods developed using globular soluble proteins have translated poorly to the rational engineering of GPCRs. To fill this gap, we propose GPCR-tm, a novel and personalized structurally driven web-based machine learning tool to study the impacts of mutations on GPCR stability. We show that GPCR-tm performs as well as or better than alternative methods, and that it can accurately rank the stability changes of a wide range of mutations occurring in various types of class A GPCRs. GPCR-tm achieved Pearson's correlation coefficients of 0.74 and 0.46 on 10-fold cross-validation and blind test sets, respectively. We observed that the (structural) graph-based signatures were the most important set of features for predicting destabilizing mutations, which points out that these signatures properly describe the changes in the environment where the mutations occur. More specifically, GPCR-tm was able to accurately rank mutations based on their effect on protein stability, guiding their rational stabilization. GPCR-tm is available through a user-friendly web server at https://biosig.lab.uq.edu.au/gpcr_tm/.

The Near-Sightedness of Many-Body Interactions in Anharmonic Vibrational Couplings.

Couplings between vibrational motions are driven by electronic interactions, and these couplings carry special significance in vibrational energy transfer, multidimensional spectroscopy experiments, and simulations of vibrational spectra. In this investigation, the many-body contributions to these couplings are analyzed computationally in the context of clathrate-like alkali metal cation hydrates, including Cs+(H2O)20, Rb+(H2O)20, and K+(H2O)20, using both analytic and quantum-chemistry potential energy surfaces. Although the harmonic spectra and one-dimensional anharmonic spectra depend strongly on these many-body interactions, the mode-pair couplings were, perhaps surprisingly, found to be dominated by one-body effects, even in cases of couplings to low-frequency modes that involved the motion of multiple water molecules. The origin of this effect was traced mainly to geometric distortion within water monomers and cancellation of many-body effects in differential couplings, and the effect was also shown to be agnostic to the identity of the ion. These outcomes provide new understanding of vibrational couplings and suggest the possibility of improved computational methods for the simulation of infrared and Raman spectra.

Automatic Content Analysis Systems: Detecting Disinformation in Social Networks

In the 21st century, the rapid rise of disinformation and propaganda has become a significant global issue, undermining democratic processes and socio-political institutions. Disinformation, defined as intentionally false or misleading information, aims to manipulate public opinion and cause economic harm. This paper explores the use of computational linguistics and machine learning methods to detect disinformation. Techniques such as text preprocessing, feature extraction, and classification algorithms (e.g., SVM, naive Bayes) are adapted for identifying fake news. Recent studies demonstrate the effectiveness of these methods in social media and news platforms, highlighting the importance of advanced models like GPT-4 in improving detection accuracy and combating the spread of disinformation.

Dynamic characterization of water hammer in gangue fly ash slurry pipelines during valve closure

In the process of coal-filling mining, the gangue fly-ash slurry (GFS) needs to be transported over a long distance to reach the gobs. The abrupt closure of the valve during the transportation of GFS can result in a water hammer that significantly endangers the stability and safety of the pipeline transport system. To study the fluctuations in pressure induced by abrupt closure of the valve, experiments on the rheological parameters of gangue-coal ash slurry were conducted. Transient numerical simulations were carried out using the computational fluid dynamics method for various valve closing times. The results indicate that, with the increase of slurry concentration, the yield stress of the slurry significantly increases. When the concentration exceeds 76%, the increase in yield stress reaches 38.4% and 35.1%, respectively. Upon valve closure, the internal pressure of the slurry in the pipeline exhibits periodic dynamic oscillations. As the duration of valve closure increases, the frequency of periodic water hammer events decreases. The maximum water hammer pressure caused by valve closure decreases with the increasing distance between the valve and the closure point. At the same time, the intensity of maximum water hammer pressure fluctuations increases with the increase in slurry concentration and flow velocity in the pipeline. The results can provide references for water hammer protection and pipeline selection during the transportation of backfill slurry in mining.

The convergence of high-accuracy three-point compact computational method for structural derivative anomalous diffusion–advection model

The convergence of high-accuracy three-point compact computational method for structural derivative anomalous diffusion–advection model

Prognostic stratification of glioblastoma patients by unsupervised clustering of morphology patterns on whole slide images furthering our disease understanding

IntroductionGlioblastoma (GBM) is a highly aggressive malignant tumor of the central nervous system that displays varying molecular and morphological profiles, leading to challenging prognostic assessments. Stratifying GBM patients according to overall survival (OS) from H&E-stained whole slide images (WSI) using advanced computational methods is challenging, but with direct clinical implications.MethodsThis work is focusing on GBM (IDH-wildtype, CNS WHO Gr.4) cases, identified from the TCGA-GBM and TCGA-LGG collections after considering the 2021 WHO classification criteria. The proposed approach starts with patch extraction in each WSI, followed by comprehensive patch-level curation to discard artifactual content, i.e., glass reflections, pen markings, dust on the slide, and tissue tearing. Each patch is then computationally described as a feature vector defined by a pre-trained VGG16 convolutional neural network. Principal component analysis provides a feature representation of reduced dimensionality, further facilitating identification of distinct groups of morphology patterns, via unsupervised k-means clustering.ResultsThe optimal number of clusters, according to cluster reproducibility and separability, is automatically determined based on the rand index and silhouette coefficient, respectively. Our proposed approach achieved prognostic stratification accuracy of 83.33% on a multi-institutional independent unseen hold-out test set with sensitivity and specificity of 83.33%.DiscussionWe hypothesize that the quantification of these clusters of morphology patterns, reflect the tumor's spatial heterogeneity and yield prognostic relevant information to distinguish between short and long survivors using a decision tree classifier. The interpretability analysis of the obtained results can contribute to furthering and quantifying our understanding of GBM and potentially improving our diagnostic and prognostic predictions.

Exploring Education as a Complex System: Computational Educational Research with Multi-Level Agent-Based Modeling

Our study employs multi-level agent-based modeling and computational techniques to explore education as a complex system. With an underlying focus that education should be underpinned by a scientific understanding of student learning, we created computational models that simulated learning dynamics in classrooms, integrating both quantitative and qualitative insights. Through these models, we conducted experiments aligned with real classroom data to address key questions, such as “How can we effectively support the academic progress of underperforming students, who are disproportionately from low socio-economic status (SES) backgrounds, to close their multi-year achievement gap in mathematics?” Our study analyzes various instructional approaches for mathematical learning, and our findings highlight the potential effectiveness of Productive Failure as an instructional approach. Considerations of the broader applicability of computational methods in advancing educational research are also provided.

Accurate Prediction of 1H NMR Chemical Shifts of Small Molecules Using Machine Learning

NMR is widely considered the gold standard for organic compound structure determination. As such, NMR is routinely used in organic compound identification, drug metabolite characterization, natural product discovery, and the deconvolution of metabolite mixtures in biofluids (metabolomics and exposomics). In many cases, compound identification by NMR is achieved by matching measured NMR spectra to experimentally collected NMR spectral reference libraries. Unfortunately, the number of available experimental NMR reference spectra, especially for metabolomics, medical diagnostics, or drug-related studies, is quite small. This experimental gap could be filled by predicting NMR chemical shifts for known compounds using computational methods such as machine learning (ML). Here, we describe how a deep learning algorithm that is trained on a high-quality, “solvent-aware” experimental dataset can be used to predict 1H chemical shifts more accurately than any other known method. The new program, called PROSPRE (PROton Shift PREdictor) can accurately (mean absolute error of <0.10 ppm) predict 1H chemical shifts in water (at neutral pH), chloroform, dimethyl sulfoxide, and methanol from a user-submitted chemical structure. PROSPRE (pronounced “prosper”) has also been used to predict 1H chemical shifts for >600,000 molecules in many popular metabolomic, drug, and natural product databases.

Effects of CO2 Geosequestration on Opalinus Clay

CO2 geosequestration is an important contributor to United Nations Sustainable Development Goal 13, i.e., Climate Action, which states a global Net-Zero CO2 emissions by 2050. A potential impact of CO2 geosequestration in depleted oil and gas reservoirs is the variations in induced pressure across the caprocks, which can lead to significant local variations in CO2 saturation. A detailed understanding of the relationship between the pressure gradient across the caprock and local CO2 concentration is of utmost importance for assessing the potential of CO2 geosequestration. Achieving this through experimental techniques is extremely difficult, and thus, we employ a coupled Computational Fluid Dynamics (CFD) and Finite Element Method (FEM) based solver to mimic sub-critical CO2 injection in Opalinus Clay under various pressure gradients across the sample. The geomechanical and multiphase flow modelling utilising Darcy Law helps evaluate local variations in CO2 concentration in Opalinus Clay. Well-validated numerical results indicate favourable sub-critical CO2 geosequestration under a positive pressure gradient across Opalinus Clay. In the absence of a positive pressure gradient, a peak CO2 concentration of 5% has been recorded, which increases substantially (above 90%) as the pressure gradient across the sample increases.

Pectoral Fin Propulsion Performance Analysis of Robotic Fish with Multiple Degrees of Freedom Based on Burst-and-Coast Swimming Behavior Stroke Ratio

The pectoral fin propulsion of a bionic robotic fish always consists of two phases: propulsion and recovery. The robotic fish moves in a burst-and-coast swimming manner. This study aims to analyze a pair of bionic robotic fish with rigid pectoral fin propulsion with three degrees of freedom and optimize the elliptical propulsion curve with the minimum recovery stroke resistance using computational fluid dynamics methods. Then, the time allocated to the propulsion and recovery phases is investigated to maximize the propulsion performance of the bionic robotic fish. The numerical simulation results show that when the time ratio of the propulsion and recovery phases is 0.5:1, the resistance during the movement of the robotic fish is effectively reduced, and the drag-reducing effect is pronounced. According to a further analysis of pressure clouds and vortex structures, the pressure difference between the upstream and downstream fins of the pectoral fin varies with different stroke ratios. The increase in recovery phase time helps to prevent premature damage to the vortex ring structure generated during the propulsion process and improves propulsion efficiency.

Dynamic multi-layer walkability model for transit-oriented movement: Nodes and Routes optimization method

This paper presents a novel approach to optimizing movement in urban areas through a dynamic multi-layer walkability model. This research uncovers new facets of walkability modeling within transit-oriented movement, aligning pedestrian pathways (Routes) with urban architecture, public spaces, and green spaces (Nodes). The dynamic multi-layer (DML) approach involves optimizing both the Nodes and Routes of the transit system using a multi-objective optimization method. This method improves accessibility and connectivity by aggregating the results of agent-based modeling for route simulations and considers multiple criteria, including greenness, distance to transit, and destination accessibility. Experimentation with a case study produced several findings that underscore the value of multi-layered models for transit movement and the power of computational methods in optimizing both Nodes and Routes. This discovery offers valuable insights into the DML process and its potential applications in the field of urban design and architecture.

Enhancing drug and cell line representations via contrastive learning for improved anti-cancer drug prioritization

Due to cancer’s complex nature and variable response to therapy, precision oncology informed by omics sequence analysis has become the current standard of care. However, the amount of data produced for each patient makes it difficult to quickly identify the best treatment regimen. Moreover, limited data availability has hindered computational methods’ abilities to learn patterns associated with effective drug-cell line pairs. In this work, we propose the use of contrastive learning to improve learned drug and cell line representations by preserving relationship structures associated with drug mechanisms of action and cell line cancer types. In addition to achieving enhanced performance relative to a state-of-the-art method, we find that classifiers using our learned representations exhibit a more balanced reliance on drug- and cell line-derived features when making predictions. This facilitates more personalized drug prioritizations that are informed by signals related to drug resistance.