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Dearomatization has emerged as a powerful tool for rapid construction of 3D molecular architectures from simple, abundant, and planar (hetero)arenes. The field has evolved beyond simple dearomatization driven by new synthetic technology development. With the renaissance of photocatalysis and expansion of the activation mode, the last few years have witnessed impressive developments in innovative photochemical dearomatization methodologies, enabling skeletal modifications of dearomatized structures. They offer truly efficient and useful tools for facile construction of highly complex structures, which are viable for natural product synthesis and drug discovery. In this review, we aim to provide a mechanistically insightful overview on these innovations based on the degree of skeletal alteration, categorized into dearomative functionalization and skeletal editing, and to highlight their synthetic utilities. [ABSTRACT FROM AUTHOR]

Accumulated experimental evidence indicated that G-protein coupled receptors (GPCRs) could form biologically relevant oligomers and hetero-oligomers possess different functional properties from monomers and homo-oligomers, for example, unique pharmacology. However, the urgent lack of crystal structures of the GPCR oligomers results in very limited knowledge about their structural and functional mechanisms. In this work, we utilized a multiscale simulation strategy coupled with principal component analysis, correlation analysis and a protein structure network to study the hetero-dimerization of the μ-OR and δ-OR. We probed the cooperative mechanism involved in their activations, the allosteric communication pathways, the impact of the interface and differences from the μ-OR homodimer. The result indicates that TM1–TM2–H8 is a stable interface, but some residues of TM7 also participate in the dimer interface. Similar to the homodimer, the hetero-dimerization of the two inactive receptors would enhance the constitutive activation of one subunit but weaken that of the other subunit, both presenting a negative cooperativity. However, in contrast to the homodimer, the hetero-dimerization of the active protomer with the inactive one would weaken the constitutive activation of the inactive unit but maintain the activity of the active subunit. In addition, the hetero-dimerization and the activation of one subunit could significantly alter the types and the numbers of residues participating in the allosteric pathway from the ligand-binding pocket to the G-protein region and the pathway between two subunits. Some important residues were identified, which play important roles in modulating activations and cooperativity between two subunits. The observations from this work indicate that the negative cooperativity should be a common feature for the homodimers and the heterodimers, but the cooperative results would be significantly different between them, depending on the activated extent of one subunit. [ABSTRACT FROM AUTHOR]

Recently, oligomers of G-protein coupled receptors (GPCRs) have been an important topic in the GPCR fields. However, knowledge about their structures and activation mechanisms is very limited due to the absence of crystal structures reported. In this work, we used multiscale simulations to study the effects of homodimerization between different conformation states on their activation, dynamic behaviors, and allosteric communication pathways for μ-OR. The results indicated that the dimerization of one inactive monomer with either one inactive monomer or one active one could enhance its constitutive activation. However, the conformation state of the other protomer (e.g., active or inactive) can influence the activated extent. The dimerization between the two inactive protomers leads to a negative cooperativity for their activation, which should contribute to the asymmetric activation of GPCR dimers observed in some experiments. On the other hand, for the active monomer, its dimerization with one inactive receptor could alleviate its deactivation, whereby negative and positive cooperativities can be observed between the two subunits of the dimer, depending on the different regions. Observations from protein structure network (PSN) analysis indicated that the dimerization of one inactive monomer with one active one would cause a significant drop in the number of main pathways from the ligand binding pocket to the G-protein coupled region for the inactive protomer, while the impact is minor for the active protomer. But, for the active monomer or the inactive one, its dimerization with one inactive monomer would significantly change the types of residues participating in the pathway with the highest frequency. [ABSTRACT FROM AUTHOR]

G-protein-coupled receptors (GPCRs) are important drug targets and generally activated by ligands. However, some experiments found that GPCRs also give rise to constitutive activity through some mutations (viz., CAM), which are usually associated with different kinds of diseases. However, the mechanisms of CAMs and their roles in interactions with drug-ligands are unclear in experiments. Herein, we used microsecond molecular dynamics simulations to study the effect of one important F282L mutation on β2AR in order to address the questions above. With the aid of principle component and correlation analysis, our results revealed that the F282L mutation could increase the instability of the overall structure, increase the dramatic fluctuations of NPxxY and extracellular loops, and decrease restraint of the helices through weakening interhelical H-bonding and correlations between residues, which could partly contribute to the constitutive activity reported by the experiments. The observations from the protein structure network (PSN) analysis indicate that the mutant exhibits less information flow than the wild β2AR and weakens the role of TM5 and TM6 in the signal transmission, but it enhances the impact of TM3 on the orthosteric pathway and TM4 on the allosteric one. In addition, the results from the virtual screening reveal that the mutant prefers to select agonists rather than antagonists, similar to the active state but opposite of the inactive state, further confirming that the F282L mutation advances the activation of β2AR. Our observations provide valuable information for understanding the mechanism of the mutation-caused constitutive activity of GPCR and related drug-design. [ABSTRACT FROM AUTHOR]

Many Gram-negative bacteria use the type I secretion system (T1SS) to translocate a wide range of substrates (type I secreted RTX proteins, T1SRPs) from the cytoplasm across the inner and outer membrane in one step to the extracellular space. Since T1SRPs play an important role in pathogen–host interactions, identifying them is crucial for a full understanding of the pathogenic mechanism of T1SS. However, experimental identification is often time-consuming and expensive. In the post-genomic era, it becomes imperative to predict new T1SRPs using information from the amino acid sequence alone when new proteins are being identified in a high-throughput mode. In this study, we report a two-level method for the first attempt to identify T1SRPs using sequence-derived features and the random forest (RF) algorithm. At the full-length sequence level, the results show that the unique feature of T1SRPs is the presence of variable numbers of the calcium-binding RTX repeats. These RTX repeats have a strong predictive power and so T1SRPs can be well distinguished from non-T1SRPs. At another level, different from that of the secretion signal, we find that a sequence segment located at the last 20–30 C-terminal amino acids may contain important signal information for T1SRP secretion because obvious differences were shown between the corresponding positions of T1SRPs and non-T1SRPs in terms of amino acid and secondary structure compositions. Using five-fold cross-validation, overall accuracies of 97% at the full-length sequence level and 89% at the secretion signal level were achieved through feature evaluation and optimization. Benchmarking on an independent dataset, our method could correctly predict 63 and 66 of 74 T1SRPs at the full-length sequence and secretion signal levels, respectively. We believe that this study will be useful in elucidating the secretion mechanism of T1SS and facilitating hypothesis-driven experimental design and validation. [ABSTRACT FROM AUTHOR]

G protein coupled receptors (GPCRs) play a crucial role in regulating signal recognition and transduction through their activation. The conformation transition in the activation pathway is of particular importance for their function. However, it has been poorly elucidated due to experimental difficulties in determining the conformations and the time limitation of conventional molecular dynamics (CMD) simulation. Thus, in this work, we employed a targeted molecular dynamic (TMD) simulation to study the activation process from an inactive structure to a fully active one for β2 adrenergic receptor (β2AR). As a reference, 110 ns CMD simulations on wild β2AR and its D130N mutant were also carried out. TMD results show that there is at least an intermediate conformation cluster in the activation process, evidenced by the principal component analysis and the structural and dynamic differences of some important motifs. It is noteworthy that the activation of the ligand binding site lags the G-protein binding site, displaying uncoupled correlation. Comparisons between the CMD and TMD results show that the D130N mutation significantly speeds up ICL2 and key ionic lock to enter into the intermediate state, which to some extent facilitates the activation involved in the NPxxY, DRY region and the separation between TM3 and TM6. However, the contribution from the D130N mutation to the activation of the ligand binding site could not be observed within the scale of 110 ns time. These observations could provide novel insights into previous studies for better understanding of the activation mechanism for β2AR. [ABSTRACT FROM AUTHOR]

A facile, economical and effective method to produce hierarchically porous nitrogen-rich carbon (HPNC) from wheat straw has been reported. Acid pretreatment is introduced before KOH activation, and plays the role of promoting the formation of thinner pore walls. Without any N-doping, the N content is as high as 5.13%. The HPNC when used as an anode for Li-ion batteries exhibits a superior specific capacity of 1470 mA h g[sup -1] at 0.037 A g[sup -1], and possesses an ultrahigh rate capability of 344 mA h g[sup -1] at 18.5 A g[sup -1]. Even at an extremely high current density of 37 A g[sup -1], the reversible capacity is still as high as 198 mA h g[sup -1]. [ABSTRACT FROM AUTHOR]