Genome-scale metabolic models have been recognised as useful tools for better understanding living organisms’ metabolism. merlin (https://www.merlin-sysbio.org/) is an open-source and user-friendly resource that hastens the models’ reconstruction process, conjugating manual and automatic procedures, while leveraging the user's expertise with a curation-oriented graphical interface. An updated and redesigned version of merlin is herein presented. Since 2015, several features have been implemented in merlin, along with deep changes in the software architecture, operational flow, and graphical interface. The current version (4.0) includes the implementation of novel algorithms and third-party tools for genome functional annotation, draft assembly, model refinement, and curation. Such updates increased the user base, resulting in multiple published works, including genome metabolic (re-)annotations and model reconstructions of multiple (lower and higher) eukaryotes and prokaryotes. merlin version 4.0 is the only tool able to perform template based and de novo draft reconstructions, while achieving competitive performance compared to state-of-the art tools both for well and less-studied organisms.

Genome-scale metabolic models have been recognized as useful tools for better understanding living organism's metabolism. Merlin (https://merlin-sysbio.org/) is an open-source and user-friendly resource that hastens these models' reconstruction process, conjugating manual, and automatic procedures, while leveraging user's expertise with a curation-oriented graphical interface. An updated and redesigned version of merlin is herein presented. Since 2015, several features were implemented in merlin, along with profound changes in the software architecture, operating flow, and graphical interface. The current version (4.0) includes the implementation of novel algorithms and third-party tools for genome functional annotation, draft assembly, model refinement, and curation. Such updates led to an increase in the user-base, resulting in multiple published works including genome metabolic (re-)annotation and model reconstruction of multiple (lower and higher) eukaryotes and prokaryotes.

Genome-Scale metabolic models (GEMs) are a relevant tool in systems biology for in silico strain optimisation and drug discovery. An easier way to reconstruct a model is to use available GEMs as templates to create the initial draft, which can be curated up until a simulation-ready model is obtained. This approach is implemented in merlin's BiGG Integration Tool, which reconstructs models from existing GEMs present in the BiGG Models database. This study aims to assess draft models generated using models from BiGG as templates for three distinct organisms, namely, Streptococcus thermophilus, Xylella fastidiosa and Mycobacterium tuberculosis. Several draft models were reconstructed using the BiGG Integration Tool and different templates (all, selected and random). The variability of the models was assessed using the reactions and metabolic functions associated with the model's genes. This analysis showed that, even though the models shared a significant portion of reactions and metabolic functions, models from different organisms are still differentiated. Moreover, there also seems to be variability among the templates used to generate the draft models to a lower extent. This study concluded that the BiGG Integration Tool provides a fast and reliable alternative for draft reconstruction for bacteria.

As the reconstruction of Genome-Scale Metabolic Models becomes standard practice in systems biology, the number of organisms having at least one metabolic model at the genome-scale is peaking at an unprecedented scale. The automation of several laborious tasks, such as gap-finding and gap-filling, allowed to develop GSMMs for poorly described organisms. However, such models' quality can be compromised by the automation of several steps, which may lead to erroneous phenotype simulations. The Biological networks constraint-based In Silico Optimization (BioISO) is a computational tool aimed at accelerating the reconstruction of Genome-Scale Metabolic Models. This tool facilitates the manual curation steps by reducing the large search spaces often met when debugging in silico biological models. BioISO uses a recursive relation-like algorithm and Flux Balance Analysis to evaluate and guide debugging of in silico phenotype simulations. The potential of BioISO to guide the debugging of model reconstructions was showcased using GSMMs available in literature and compared with the results of two other state-of-the-art gap-filling tools (Meneco and fastGapFill). Furthermore, BioISO was used as Meneco's gap-finding algorithm to reduce the number of proposed solutions (reaction sets) for filling the gaps. BioISO was implemented as a webserver available at https://bioiso.bio.di.uminho.pt; and integrated into merlin as a plugin. BioISO's implementation as a Python package can also be retrieved from https://github.com/BioSystemsUM/BioISO.

The non-caloric sweeteners market is catching up with the market of conventionally used sugars due to the benefits of preventing obesity, tooth decay and other health problems. Developing strategies for designing easier-to-produce novel molecules with a sweet taste and less toxicity are up-todate motivations for the food industry. In this sense, Machine Learning (ML) approaches have been reported as cutting-edge technologies to guide the design of new molecules towards specific objectives, including sweet taste.The largest known dataset of sweet molecules is here provided. The dataset contains fully integrated 9541 sweeteners and 1141 bitterants from FooDB, FlavorDB and literature. This robust dataset allowed the development of standard Machine and Deep Learning pipelines towards conceiving Structure-Activity Relationships (SAR) between molecules and sweetness.In this work, we showcase that Textual Convolutional Neural Networks (TextCNN), Graph Convolutional Networks (GCN), and Deep Neural Networks (DNNs) outperformed most of traditional "shallow" learning approaches. These Deep Learning (DL) models produced platforms to guide the design of new sweeteners and repurposing existing compounds.Sixty million compounds from PubChem were evaluated using these models. Herein, we deliver a dataset of 67724 compounds that present high probabilities of being sweet. Quick searches in literature allowed us to find 13 molecules reported as potent sweetening agents, revealing that our approach is suitable for finding new sweeteners, valuable to expand food chemistry databases, repurposing existing chemicals and designing novel molecules with a sweet taste.

Genome-scale metabolic models (GEMs) are essential tools for in silico phenotype prediction and strain optimisation. The most straightforward GEMs reconstruction approach uses published models as templates to generate the initial draft, requiring further curation. Such an approach is used by BiGG Integration Tool (BIT), available for merlin users. This tool uses models from BiGG Models database as templates for the draft models. Moreover, BIT allows the selection between different template combinations. The main objective of this study is to assess the draft models generated using this tool and compare them BIT, comparing these to CarveMe models, both of which use the BiGG database, and curated models. For this, three organisms were selected, namely Streptococcus thermophilus, Xylella fastidiosa and Mycobacterium tuberculosis. The models’ variability was assessed using reactions and genes’ metabolic functions. This study concluded that models generated with BIT for each organism were differentiated, despite sharing a significant portion of metabolic functions. Furthermore, the template seems to influence the content of the models, though to a lower extent. When comparing each draft with curated models, BIT had better performances than CarveMe in all metrics. Hence, BIT can be considered a fast and reliable alternative for draft reconstruction for bacteria models.