Systems biology has experienced dramatic growth in the number, size, and complexity of computational models. To reproduce simulation results and reuse models, researchers must exchange unambiguous model descriptions. We review the latest edition of the Systems Biology Markup Language (SBML), a format designed for this purpose. A community of modelers and software authors developed SBML Level 3 over the past decade. Its modular form consists of a core suited to representing reaction‐based models and packages that extend the core with features suited to other model types including constraint‐based models, reaction‐diffusion models, logical network models, and rule‐based models. The format leverages two decades of SBML and a rich software ecosystem that transformed how systems biologists build and interact with models. More recently, the rise of multiscale models of whole cells and organs, and new data sources such as single‐cell measurements and live imaging, has precipitated new ways of integrating data with models. We provide our perspectives on the challenges presented by these developments and how SBML Level 3 provides the foundation needed to support this evolution.
BackgroundIn 2017 World Health Organization announced the list of the most dangerous superbugs and among them is Pseudomonas aeruginosa, which is an antibiotic resistant opportunistic human pathogen as well as one of the ‘SKAPE’ pathogens. The central problem is that it affects patients suffering from AIDS, cystic fibrosis, cancer, burn victims etc. P. aeruginosa creates and inhabits surface-associated biofilms. Biofilms increase resistance to antibiotics and host immune responses, because of those current treatments are not effective. It is imperative to find new antibacterial treatment strategies against P. aeruginosa, but detailed molecular properties of the LasR protein are not clearly known to date. In the present study, we tried to analyse the molecular properties of the LasR protein as well as the mode of its interactions with autoinducer (AI) the N-3-oxododecanoyl homoserine lactone (3-0-C12-HSL).ResultsWe performed docking and molecular dynamics (MD) simulations of the LasR protein of P. aeruginosa with the 3-0-C12-HSL ligand. We assessed the conformational changes of the interaction and analysed the molecular details of the binding of the 3-0-C12-HSL with LasR. A new interaction site of the 3-0-C12-HSL with LasR protein was found, which involves interaction with conservative residues from ligand binding domain (LBD), beta turns in the short linker region (SLR) and DNA binding domain (DBD). It will be referenced as the LBD-SLR-DBD bridge interaction or “the bridge”. We have also performed LasR monomer protein docking and found a new form of dimerization.ConclusionsThis study may offer new insights for future experimental studies to detect the interaction of the autoinducer with “the bridge” of LasR protein and a new interaction site for drug design.
Background: Pseudomonas aeruginosa is one of the most dangerous superbugs in the list of
Antibiotic resistance is a global problem nowadays and in 2017 the World Health Organization published the list of bacteria for which treatment are urgently needed, where Pseudomonas aeruginosa is of critical priority. Current therapies lack efficacy because this organism creates biofilms conferring increased resistance to antibiotics and host immune responses. The strategy is to "not kill, but disarm" the pathogen and resistance will be developed slowly. It has been shown that LasI/LasR system is the main component of the quorum sensing system in P. aeruginosa. LasR is activated by the interaction with its native autoinducer. A lot flavones and their derivatives are used as antibacterial drug compounds. The purpose is to search compounds that will inhibit LasR. This leads to the inhibition of the synthesis of virulence factors thus the bacteria will be vulnerable and not virulent. We performed virtual screening using multiple docking programs for obtaining consensus predictions. The results of virtual screening suggest benzamides which are synthetical derivatives of flavones as potential inhibitors of transcriptional regulator LasR. These are consistent with recently published experimental data, which demonstrate the high antibacterial activity of benzamides. The compounds interact with the ligand binding domain of LasR with higher binding affinity than with DNA binding domain. Among the selected compounds, by conformational analysis, it was found that there are compounds that bind to the same amino acids of ligand binding domain as the native autoinducer. This could indicate the possibility of competitive interaction of these compounds. A number of compounds that bind to other conservative amino acids ligand binding domain have also been discovered, which will be of interest for further study. Selected compounds meet the criteria necessary for their consideration as drugs and can serve as a basis for conducting further in vitro / in vivo experiments. It could be used for the development of modern anti-infective therapy based on the quorum sensing system of P. aeruginosa.
Pseudomonas aeruginosa is one of the most dangerous superbugs and is responsible for both acute and chronic infection. Current therapies are not effective because of biofilms that increase antibiotic resistance. Bacterial virulence and biofilm formation are regulated through a system called quorum sensing, which includes transcriptional regulators LasR and RhIR. These regulators are activated by their own natural autoinducers. Targeting this system is a promising strategy to combat bacterial pathogenicity. Flavonoids are very well known for their antimicrobial activity and taxifolin is one of them. It is also known that flavonoids inhibit Pseudomonas aeruginosa biofilm formation, but the mechanism of action is unknown. In the present study, we tried to analyse the mode of interactions of LasR with taxifolin. We used a combination of molecular docking, molecular dynamics simulations and machine learning techniques, which includes principal component and cluster analysis to study the interaction of the LasR protein with taxifolin. We show that taxifolin has two binding modes. One binding mode is the interaction with ligand binding domain. The second mode is the interaction with the "bridge", which is a cryptic binding site. It involves conserved amino acid interactions from multiple domains. Biochemical studies show hydroxyl group of ring A in flavonoids is necessary for inhibition. In our model the hydroxyl group ensures the formation of many hydrogen bonds during the second binding mode. Microsecond simulations also show the stability of the formed complex. This study may offer insights on how taxifolin inhibits LasR and the quorum sensing circuitry.
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