Synergistic Antimicrobial Mechanism of the Ultrashort Antimicrobial Peptide R3W4V with a Tadpole-like Conformation.

Antimicrobial peptides (AMPs) are promising candidates in combating multidrug-resistant microorganisms because of their unique mode of action. Among these peptides, ultrashort AMPs (USAMPs) possess sequences containing less than 10 amino acids and have some advantages over traditional AMPs. However, one of the main limitations of designing novel and highly active USAMPs is that their mechanism of action at the molecular level is not well-known. In this article, we report the antimicrobial mechanism of the USAMP verine (R3W4V) with high antibacterial activity against Escherichia coli. Here, by using well-tempered bias-exchange metadynamics simulations and long-time conventional molecular dynamics simulations, we evaluated whether verine exhibits the same antimicrobial mode of action as that of traditional AMPs. The single verine-membrane system exhibited a relatively flat surface with multiple shallow minima separated by very small energy barriers and adopted highly dynamic structural ensembles. Although the verine sequence is very short, it can still exist briefly in the center of the cell membrane in a transmembrane state. As the concentration of verine increased, the transmembrane conformation was relatively stabilized in the membrane center or proceeded toward the membrane bottom. The lipid bilayer membrane showed relatively large deformation, including the phospholipid head groups embedded inside the lipid hydrophobic center, accompanied by a flip-flop of some lipids. Simulation results indicated that verine has a specific mechanism of action different from that of traditional AMPs. Based on this antimicrobial mechanism of verine, we can design new high-potential USAMPs by enhancing the structural stability of the transmembrane state.

The sweet taste receptors in Lemuriformes respond to aspartame, a non-nutritive sweetener and critical residues mediating their taste.

Aspartame is a high potency artificial sweetener which is popularly used in foods and beverages. The species-dependent sweet taste toward aspartame has not been completely understood. In a recent publication, we reported that the prosimians Lemuriformes species, which are proposed as aspartame nontasters, could taste aspartame based on the sequence and structure analysis. In this study, by mutagenesis, cell-based functional analysis and molecular simulations, we reveal that Lemuriformes species can respond to aspartame at the cell-based receptor activity level. Furthermore, it is proved that the conserved critical residues D142 and S40 mediate the species-dependent sweet taste toward aspartame. This research provides a deeper insight on the species taste, structure-activity relationship and evolution for eliciting the sweetness of this important synthetic sweetener.

Triple-Responsive, Multimodal, Visual Electronic Skin toward All-in-One Health Management for Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is one of the most common metabolic disorders during pregnancy, leading to serious complications for pregnant women and a threat to life safety of infants. Therefore, it is particularly important to establish a multipurpose monitoring pathway to important physiological indicators of pregnant women. In this work, three kinds of double network hydrogels are prepared with poly(vinyl alcohol) (PVA), borax, and cellulose ethers with varying substituents of methyl (methyl cellulose, MC), hydroxypropyl (hydroxypropyl cellulose, HPC), or both (hydroxypropyl methyl cellulose, HPMC), respectively. The corresponding toughness (143.9, 102.3, and 135.9 kJ cm-3) and conductivity (0.69, 0.45, and 0.51 S m-1) of the hydrogels demonstrate that PB-MC was endowed with the prominent performance. Molecular dynamics simulations further revealed the essence that hydrogen bond interactions between PVA and cellulose ethers play a critical role in regulating the structure and properties of hydrogels. Thermochromic capsule powders (TCPs) were subsequently doped in to achieve a composite hydrogel (TCPs@PB-MC) to indicate the change in human body temperature. Furthermore, the process of the TCPs@PB-MC response to glucose, pH, and temperature was tracked in-depth through the electrochemical window. This work provides a novel strategy for all-in-one health management of GDM.

Interaction of Asn297-Linked Glycan Ligands with the Fc Fragment of the Immunoglobulin Class G1: A Molecular Dynamics Simulation Study.

The allosteric modulation of the homodimeric H10-03-6 protein to glycan ligands L1 and L2, and the STAB19 protein to glycan ligands L3 and L4, respectively, has been studied by molecular dynamics simulations and free energy calculations. The results revealed that the STAB19 protein has a significantly higher affinity for L3 (-11.38 ± 2.32 kcal/mol) than that for L4 (-5.51 ± 1.92 kcal/mol). However, the combination of the H10-03-6 protein with glycan L2 (1.23 ± 6.19 kcal/mol) is energetically unfavorable compared with that of L1 (-13.96 ± 0.35 kcal/mol). Further, the binding of glycan ligands L3 and L4 to STAB19 would result in the significant closure of the two CH2 domains of the STAB19 conformation with the decrease of the centroid distances between the two CH2 domains compared with the H10-03-6/L1/L2 complex. The CH2 domain closure of STAB19 relates directly to the formation of new hydrogen bonds and hydrophobic interactions between the residues Ser239, Val240, Asp265, Glu293, Asn297, Thr299, Ser337, Asp376, Thr393, Pro395, and Pro396 in STAB19 and glycan ligands L3 and L4, which suggests that these key residues would contribute to the specific regulation of STAB19 to L3 and L4. In addition, the distance analysis revealed that the EF loop in the H10-03-6/L1/L2 model presents a high flexibility and partial disorder compared with the stabilized STAB19/L3/L4 complex. These results will be helpful in understanding the specific regulation through the asymmetric structural characteristics in the CH2 and CH3 domains of the H10-03-6 and STAB19 proteins.

Research Progress on Small Molecular Inhibitors of the Type 3 Secretion System.

The overuse of antibiotics has led to severe bacterial drug resistance. Blocking pathogen virulence devices is a highly effective approach to combating bacterial resistance worldwide. Type three secretion systems (T3SSs) are significant virulence factors in Gram-negative pathogens. Inhibition of these systems can effectively weaken infection whilst having no significant effect on bacterial growth. Therefore, T3SS inhibitors may be a powerful weapon against resistance in Gram-negative bacteria, and there has been increasing interest in the research and development of T3SS inhibitors. This review outlines several reported small-molecule inhibitors of the T3SS, covering those of synthetic and natural origin, including their sources, structures, and mechanisms of action.

Molecular dynamics simulation studies on the specific regulation of PTPN18 to the HER2 phospho-peptides.

The specific regulation of PTPN18 protein to three HER2 phospho-peptides has been studied by molecular dynamics simulations and free energy calculations. The results revealed that the three HER2 phospho-peptides binding to the PTPN18 catalytic domain is energetically favorable due to substrate specificity of PTPN18, and moreover, the PTPN18 protein have significantly higher affinity to pY1248 peptide (-45.22 kcal/mol) than that of pY1112 (-25.3 kcal/mol) and pY1196 (-31.86 kcal/mol) peptides. Further, the binding of HER2 phospho-peptides to PTPN18 have also caused the closure of WPD-loop with the decrease of the centroid distances between the P-loop and the WPD loop. The WPD-loop closure of PTPN18 relates directly to the new hydrogen bond and hydrophobic interaction formations between the residues Tyr62, Asp64, Val65, Ala231, Arg235, and Ala273 in PTPN18 and Tyr(PO3) in the HER2 phospho-peptides, which suggests that these key residues would contribute to the specific regulation of PTPN18 to the substrates. The correlation analysis revealed the allosteric communication networks from the pY binding loop to the WPD loop through the structural change and the residue interactions in PTPN18. These results will be helpful to understand the specific regulation through the allosteric communication network in the PTPN18 catalytic domain.

A mitochondria-targeting fluorescent sensor for on-off-on response to Cu2+ and ATP in cells and zebrafish.

Cupric ion (Cu2+) and adenosine triphosphate (ATP) are functionally important in mitochondria and play essential roles in many important biological processes. In this work, a mitochondria-targeting fluorescent molecule Mito-A was used as a probe to detect Cu2+ and ATP. The results showed remarkable fluorescence quenching of Mito-A in the presence of Cu2+, and then the quenched fluorescence solution gradually recovered due to the ATP binding to Cu2+ from the structure of the molecule. Mito-A has high sensitivity to Cu2+ and ATP, with limits of detection (LOD) close to 40 nM and 0.43 µM, respectively. Cell imaging experiments showed that Mito-A has good mitochondria-targeting capabilities, and can be successfully employed for imaging Cu2+ and ATP in living cells and zebrafish.

Self-assembly of chemically modified graphene sheets in an external magnetic field.

The rapid developments of effective self-assembly technologies indicated that ordered structures could be produced using external field inducement. We designed the alignment of graphene oxide nanosheets grafted with the modified ferroferric oxide by the application of a magnetic field. The results indicated that the morphologies of graphene oxide went through some changes from disordered to semi-ordered in the final and, highly oriented wrinkled structures. The orientation mechanism of graphene oxide demonstrated that the geometric features of the wrinkles were related to the edge stresses and the elastic stiffness of the sheets, magnetic force of magnetic field to magnetic-particles. The prepared reduced graphene oxide fibers indicated that the sheets with magnetic precipitates underwent shrinkage in the radial direction when an external magnetic field was exerted and the interior sheets aligned along the direction of the magnetic field, which was supported by the proposed theories. It is expected that the research could contribute to the applications of flexible graphene-based materials in preparation and controlling the formation of wrinkles in single layer graphene.

Synergetic effects of graphene-CoPc/silk fibroin three-dimensional porous composites as catalysts for acid red G degradation.

The disposal of dye wastewater is one of the hotspots of scientific research. Upon combining the ability of graphene to accelerate the hydroxyl radical generation with the Fenton system, it has shown a faster degradation rate and can be recycled, showing greater degradation efficiency than the traditional dye treatment method. Herein, a catalytic system based on the regenerated silk fibroin (SF) gel integrated with cobalt tetraaminophthalocyanine (CoTAPc)-grafted-reduced graphene oxide (RGO) sheets were fabricated, and its catalytic activity was assessed via the degradation of acid red G (ARG) at varying catalyst and H2O2 dosages, pH values, and temperatures. The results revealed that the three-dimensional (3D) porous RGO-CoTAPc/SF gel exhibited a much stronger catalytic behavior than the other arbitrary components due to its high surface area and synergetic hydroxyl radical generation efficiency, with the dye removal ratio by RGO-CoTAPc/SF being higher in an acidic medium than in an alkaline medium. It also increases with the increase in temperature and RGO-CoTAPc/SF and H2O2 dosages. Further, the catalytic oxidation process of ARG was determined, and the possible degradation mechanism of ARG has been discussed. Our results suggest that the composite materials with high catalytic activity can provide a reference for future Fenton-like catalytic systems.

Density functional theory studies on the inclusion complexes of cyclic decapeptide with 1-phenyl-1-propanol enantiomers.

Cyclic peptides are exciting novel hosts for chiral and molecular recognition. In this work, the inclusion complexes of cyclic decapeptide (CDP) with the 1-phenyl-1-propanol enantiomers (E-PP) are firstly studied using the density functional theory (DFT) B3LYP method. Our calculated results indicated that S(-)-1-phenyl-1-propanol (S-PP) could form a more stable inclusion complex with CDP than that of R(+)-1-phenyl-1-propanol (R-PP). The obvious differences in binding energy and thermodynamics data suggest that the cyclic decapeptide could differentiate the two enantiomers. Furthermore, molecular dynamics simulation results have supported the conclusions obtained by DFT. The current investigation shows that cyclic peptide is a desirable host molecule for chiral and molecular recognition.