Agonist activation to open the Gα subunit of the GPCR-G protein precoupled complex defines functional agonist activation of TAS2R5.

G protein-coupled receptors (GPCRs) regulate multiple cellular responses and represent highly successful therapeutic targets. The mechanisms by which agonists activate the G protein are unclear for many GPCR families, including the bitter taste receptors (TAS2Rs). We ascertained TAS2R5 properties by live cell-based functional assays, direct binding affinity measurements using optical resonators, and atomistic molecular dynamics simulations.

The G Protein-First Mechanism for Activation of the Class B Glucagon-like Peptide 1 Receptor Coupled to N-Terminal Domain-Mediated Conformational Progression.

Recently, there has been a great deal of excitement about new glucagon-like peptide 1 receptor (GLP-1R) agonists (e.g., semaglutide and tirzepatide) that have received FDA approval for type 2 diabetes and obesity.

Molecular Dynamics Investigation into CerENP's Effect on the Lipid Matrix of Stratum Corneum.

The extracellular lipid matrix in the stratum corneum (SC) plays a critical role in skin barrier functionality, comprising three primary components: ceramides, cholesterol, and free fatty acids. The diverse ceramides, differentiated by molecular structures such as hydroxylations and varying chain lengths, are essential for the lipid matrix's structural integrity. Recently, a new subclass of ceramide, 1--acylceramide NP (CerENP), has been identified; however, its precise role in the lipid matrix of the SC is still elusive.

Copper(II) coordination to the intrinsically disordered region of SARS-CoV-2 Nsp1.

The intrinsically disordered C-terminal peptide region of severe acute respiratory syndrome coronavirus 2 nonstructural protein-1 (Nsp1-CT) inhibits host protein synthesis by blocking messenger RNA (mRNA) access to the 40S ribosome entrance tunnel. Aqueous copper(II) ions bind to the disordered peptide with micromolar affinity, creating a possible strategy to restore protein synthesis during host infection. Electron paramagnetic resonance (EPR) and tryptophan fluorescence measurements on a 10-residue model of the disordered protein region (Nsp1-CT), combined with advanced quantum mechanics calculations, suggest that the peptide binds to copper(II) as a multidentate ligand.

Molecular Dynamics Studies of Atomistically Determined Fibrillar Assemblies: Comparison of the Rippled β-Sheet, Pleated β-Sheet, and Herringbone Structures.

Pauling and Corey expected that a racemic mixture would result in a rippled β-sheet, however, it has been known from experiments that the racemic mixtures of triphenylalanine lead to a herringbone structure. Because of the theoretical limitations concerning crystal structures such as rippled β-sheet, it is inevitable to understand how the interplay of the amino acids prefers a specific structural motif. In this paper we use molecular dynamics to understand the sequence- and enantiomer-dependent structures by comparisons between rippled β-sheet and pleated β-sheet, solvated and anhydrous rippled β-sheet, and rippled β-sheet and the herringbone structure, based on thermodynamics and structures at the atomic level.

Manipulating the diffusion energy barrier at the lithium metal electrolyte interface for dendrite-free long-life batteries.

Constructing an artificial solid electrolyte interphase (SEI) on lithium metal electrodes is a promising approach to address the rampant growth of dangerous lithium morphologies (dendritic and dead Li) and low Coulombic efficiency that plague development of lithium metal batteries, but how Li transport behavior in the SEI is coupled with mechanical properties remains unknown. We demonstrate here a facile and scalable solution-processed approach to form a LiN-rich SEI with a phase-pure crystalline structure that minimizes the diffusion energy barrier of Li across the SEI. Compared with a polycrystalline LiN SEI obtained from conventional practice, the phase-pure/single crystalline LiN-rich SEI constitutes an interphase of high mechanical strength and low Li diffusion barrier.

How Permanent Are the Permanent Macrodipoles of Anthranilamide Bioinspired Molecular Electrets?

Dipoles are ubiquitous, and their impacts on materials and interfaces affect many aspects of daily life. Despite their importance, dipoles remain underutilized, often because of insufficient knowledge about the structures producing them. As electrostatic analogues of magnets, electrets possess ordered electric dipoles.

Understanding Ionic Diffusion Mechanisms in LiS Coatings for Solid-State Batteries: Development of a Tailored Reactive Force Field for Multiscale Simulations.

In order to investigate LiS as a potential protective coating for lithium anode batteries using superionic electrolytes, we need to describe reactions and transport for systems at scales of >10,000 atoms for time scales beyond nanoseconds, which is most impractical for quantum mechanics (QM) calculations. To overcome this issue, here, we first report the development of the reactive analytical force field (ReaxFF) based on density functional theory (DFT) calculations on model systems at the PBE0/TZVP and M062X/TZVP levels. Then, we carry out reactive molecular dynamics simulations (RMD) for up to 20 ns to investigate the diffusion mechanisms in bulk LiS as a function of vacancy density, determining the activation barrier for diffusion and conductivity.

Fully activated structure of the sterol-bound Smoothened GPCR-Gi protein complex.

Smoothened (SMO) is an oncoprotein and signal transducer in the Hedgehog signaling pathway that regulates cellular differentiation and embryogenesis. As a member of the Frizzled (Class F) family of G protein-coupled receptors (GPCRs), SMO biochemically and functionally interacts with Gi family proteins. However, key molecular features of fully activated, G protein-coupled SMO remain elusive.

Structure and Molecular Mechanism of Signaling for the Glucagon-like Peptide-1 Receptor Bound to Gs Protein and Exendin-P5 Biased Agonist.

The glucagon-like peptide-1 receptor (GLP-1R) is a key regulator of blood glucose and a prime target for the treatment of type II diabetes and obesity with multiple public drugs. Here we present a comprehensive computational analysis of the interactions of the activated GLP-1R-Gs signaling complex with a G protein biased agonist, Exendin P5 (ExP5), which possesses a unique N-terminal sequence responsible for the signal bias. Using a refined all-atom model of the ExP5-GLP-1R-Gs complex in molecular dynamics (MD) simulations, we propose a novel mechanism of conformation transduction in which the unique interaction network of ExP5 N-terminus propagates the binding signal across an array of conserved residues at the transmembrane domain to enhance Gs protein coupling at the cytoplasmic end of the receptor.

Discovery and Binding Mechanism of Pyrazoloisoquinoline-Based Novel β-Arrestin Inverse Agonists of the Kappa-Opioid Receptor.

Chronic exposure to stress or unwanted stimuli has been known to activate kappa opioid receptor/dynorphin (KOR/DYN) systems, which could induce depressive states and develop into some psychiatric disorders. Here, we report the first discovery of pyrazoloisoquinoline-based novel KOR β-arrestin inverse agonists through synthesis, structure-activity relationships, optimization, and the biological evaluations of μ/κ/δ opioid receptor activities with cAMP and β-arrestin recruitment assays. The optimized compound shows potent and selective β-arrestin inverse agonism at KOR with an EC value of 9.

G protein coupling and activation of the metabotropic GABA heterodimer.

Metabotropic γ-aminobutyric acid receptor (GABAR), a class C G protein-coupled receptor (GPCR) heterodimer, plays a crucial role in the central nervous system. Cryo-electron microscopy studies revealed a drastic conformational change upon activation and a unique G protein (GP) binding mode. However, little is known about the mechanism for GP coupling and activation for class C GPCRs.

Structures and Agonist Binding Sites of Bitter Taste Receptor TAS2R5 Complexed with Gi Protein and Validated against Experiment.

Bitter taste receptors (TAS2Rs) function in taste perception, but are also expressed in many extraoral tissues, presenting attractive therapeutic targets. TAS2R5s expressed on human airway smooth muscle cells can induce bronchodilation for treating asthma and other obstructive diseases. But TAS2R5s display low agonist affinity and the lack of a 3D structure has hindered efforts to design more active ligands.

Artificial Taste Buds: Bioorthogonally Ligated Gustatory-Neuronal Multicellular Hybrids Enabling Intercellular Taste Signal Transmission.

Heterogeneous tissue models require the assembly and co-culture of multiple types of cells. Our recent work demonstrated taste signal transmission from gustatory cells to neurons by grafting single-stranded DNA into the cell membrane to construct multicellular assemblies. However, the weak DNA linkage and low grafting density allowed the formation of large gustatory cell self-aggregates that cannot communicate with neurons efficiently.

Predicted structure of fully activated human bitter taste receptor TAS2R4 complexed with G protein and agonists.

Bitter taste is sensed by bitter taste receptors (TAS2Rs) that belong to the G protein-coupled receptor (GPCR) superfamily. In addition to bitter taste perception, TAS2Rs have been reported recently to be expressed in many extraoral tissues and are now known to be involved in health and disease. Despite important roles of TAS2Rs in biological functions and diseases, no crystal structure is available to help understand the signal transduction mechanism or to help develop selective ligands as new therapeutic targets.

Subnanomolar FRET-Based DNA Assay Using Thermally Stable Phosphorothioated DNA-Functionalized Quantum Dots.

Quantum dots (QDs) can serve as an attractive Förster resonance energy transfer (FRET) donor for DNA assay due to their excellent optical properties. However, the specificity and sensitivity of QD-based FRET analysis are prominently reduced by nonspecific DNA adsorption and poor colloidal stability during DNA hybridization, which hinders the practical applications of QDs as a biosensing platform. Here, we report subnanomolar FRET assay of DNA through the stabilization of DNA/QD interface using DNA-functionalized QDs with phosphorothioated single-stranded DNA (pt-ssDNA) as a multivalent ligand in an aqueous solution.

Directed Nanoscale Self-Assembly of Natural Photosystems on Nitrogen-Doped Carbon Nanotubes for Solar-Energy Harvesting.

Natural photosystems (PSs) have received much attention as a biological solar energy harvester because of their high quantum efficiency for energy transfer. However, the PSs hybridized with solid electrodes exhibit low light-harvesting efficiencies because of poor interface properties and random orientations of PSs, all of which interfere with efficient charge extraction and transfer. Herein, we report the linker-free, oriented self-assembly of natural PSs with nitrogen-doped carbon nanotubes (NCNTs) via electrostatic interaction.

Gold Binding Peptide Identified from Microfluidic Biopanning: An Experimental and Molecular Dynamics Study.

Biopanning refers to the processes of screening peptides with a high affinity to a target material. Microfluidic biopanning has advantages compared to conventional biopanning which requires large amounts of the target material and involves inefficient multiple pipetting steps to remove nonspecific or low-affinity peptides. Here, we fabricate a microfluidic biopanning system to identify a new gold-binding peptide (GBP).

Low-power and low-drug-dose photodynamic chemotherapy via the breakdown of tumor-targeted micelles by reactive oxygen species.

Tumor-targeted delivery of anticancer agents using nanocarriers has been explored to increase the therapeutic index of cancer chemotherapy. However, only a few nanocarriers are clinically available because the physiological complexity often compromises their ability to target, penetrate, and control the release of drugs. Here, we report a method which dramatically increases in vivo therapeutic drug efficacy levels through the photodynamic degradation of tumor-targeted nanocarriers.

Polyglycerolated nanocarriers with increased ligand multivalency for enhanced in vivo therapeutic efficacy of paclitaxel.

Despite the excellent biocompatibility and antifouling effect of poly(ethylene glycol) (PEG), the high steric hindrance, limited chemical functionality, and low ligand multivalency of PEGylated nanocarriers often lead to inefficient cell targeting and intracellular trafficking. Hence, a new structure of hydrophilic corona allowing a higher ligand density without loss of excellent biocompatibility is highly desirable. Here we introduce tumor-targeted polyglycerolated (PGylated) nanocarriers that dramatically enhance the in vivo therapeutic efficacy of incorporated paclitaxel simply by increasing the surface density of hydrophobic tumor-targeting ligands.

Bioinspired Design of an Immobilization Interface for Highly Stable, Recyclable Nanosized Catalysts.

Immobilization of nanometer-sized metal catalysts into porous substrates can stabilize the catalysts and allow their recycled uses, while immobilization often sacrifices the active surface of catalysts and degenerates the local microenvironments, resulting in the reduction of the catalytic activity. To maintain a high activity of immobilized nanocatalysts, it is critically important to design an interface that minimizes the contact area and favors reaction chemistry. Here we report on the application of mussel-inspired adhesion chemistry to the formation of catalytic metal nanocrystal-polydopamine hybrid materials that exhibit a high catalytic efficiency during recycled uses.

Substrate-mediated proton relay mechanism for the religation reaction in topoisomerase II.

The DNA religation reaction of yeast type II topoisomerase (topo II) was investigated to elucidate its metal-dependent general acid/base catalysis. Quantum mechanical/molecular mechanical calculations were performed for the topo II religation reaction, and the proton transfer pathway was examined. We found a substrate-mediated proton transfer of the topo II religation reaction, which involves the 3' OH nucleophile, the reactive phosphate, water, Arg781, and Tyr782.