Self-assembly of rigid amphiphilic graft cyclic-brush copolymers to nanochannels using dissipative particle dynamics simulation.

The synthesis of specific artificial nanochannels remains a formidable challenge in the field of nanomaterials and synthetic chemistry. In particular, the preparation of artificial nanochannels using amphiphilic graft cyclic-brush copolymers (AGCCs) as monomers has garnered substantial attention. Nevertheless, because of the constrained time and length scales inherent in traditional molecular dynamics simulations, a comprehensive theoretical understanding of the morphological regulation mechanism governing the self-assembly of AGCCs into nanochannels remains elusive. In this study, we employed the dissipative particle dynamics (DPD) method to explore the self-assembly mechanism considering factors such as the DPD interaction parameters, concentrations, and sizes of AGCCs. By calculating the phase diagrams, we predicted the emergence of four distinct nanochannel types: short independent, long independent, parallel, and disordered channels. Importantly, the formation of these nanochannels is highly contingent on specific environmental conditions. Furthermore, we extensively discussed self-assembly processes that lead to different types of nanochannels. The self-assembly of AGCCs is revealed as a multistep process primarily influenced by the interaction parameters. However, while the monomer size and concentration do not introduce novel self-assembly morphologies, they do influence the final aggregation state. The elucidation of the self-assembly mechanism presented in this study deepens our understanding of AGCC nanochannel formation. Consequently, this is a valuable guide for the preparation of copolymer materials with specific functionalities, offering insights into targeted copolymer material design.

A Three-Dimensional Open-Framework Tin(II) Sulfate with Near-Unity Photoluminescence Quantum Yield.

A new open-framework tin(II) sulfate, formulated as C4H12N2·Sn(SO4)2·H2O, was prepared under the structure-directing effect of piperazine. This compound features a 3D structure with 16-ring channels. Under ultraviolet light irradiation, it emits bright yellow luminescence with a near-unity photoluminescence quantum yield. Theoretical calculations were carried out to understand the luminescence mechanism.

A theoretical study of the mechanism of cationic polymerization of isobutylene catalysed by EtAlCl2/t-BuCl with bis(2-chloroethyl)ether in hexanes.

The mechanism of cationic polymerization of isobutylene catalyzed by t-BuCl/ethylaluminum dichloride (EADC) combined with bis(2-chloroethyl)ether (CEE) in n-hexane solvent has been investigated using ab initio molecular dynamics (AIMD) and metadynamics (MTD) simulations. The results indicated that the polyisobutylene (PIB) initiation stage involves a clear two-step mechanism. Calculation of the free energy landscapes of the other two ether reactions reveals that the energy barriers of diisopropyl ether (i-Pr2O) and 2-chloroethyl ethyl ether (CEEE) are much higher than those of CEE, which is consistent with the experimental results. During the chain propagation phase, the required free energy barrier gradually decreases and tends to reach equilibrium as the chain length increases. Finally, the oxonium mechanism during the chain initiation stage was investigated by calculating the 1H NMR spectra and MTD simulation. Our calculations can confirm that the existence of tert-butyloxonium ions during the reaction is possible. Their contribution to the whole reaction is further discussed.

Data Mining and Graph Network Deep Learning for Band Gap Prediction in Crystalline Borate Materials.

Crystalline borates are an important class of functional materials with wide applications in photocatalysis and laser technologies. Obtaining their band gap values in a timely and precise manner is a great challenge in material design due to the issues of computational accuracy and cost of first-principles methods. Although machine learning (ML) techniques have shown great successes in predicting the versatile properties of materials, their practicality is often limited by the data set quality. Here, by using a combination of natural language processing searches and domain knowledge, we built an experimental database of inorganic borates, including their chemical compositions, band gaps, and crystal structures. We performed graph network deep learning to predict the band gaps of borates with accuracy, and the results agreed favorably with experimental measurements from the visible-light to the deep-ultraviolet (DUV) region. For a realistic screening problem, our ML model could correctly identify most of the investigated DUV borates. Furthermore, the extrapolative ability of the model was validated against our newly synthesized borate crystal Ag3B6O10NO3, supplemented by the discussion of an ML-based material design for structural analogues. The applications and interpretability of the ML model were also evaluated extensively. Finally, we implemented a web-based application, which could be utilized conveniently in material engineering for the desired band gap. The philosophy behind this study is to use cost-effective data mining techniques to build high-quality ML models, which can provide useful clues for further material design.

Design, synthesis and biological evaluation of purine-based derivatives as novel JAK2/BRD4(BD2) dual target inhibitors.

Based on the pharmacological synergy of JAK2 and BRD4 in the NF-κB pathway and positive therapeutic effect of combination of JAK2 and BRD4 inhibitors in treating MPN and inflammation. A series of unique 9H-purine-2,6-diamine derivatives that selectively inhibited Janus kinase 2 (JAK2) and BRD4(BD2) were designed, prepared, and evaluated for their in vitro and in vivo potency. Among them, compound 9j exhibited acceptable inhibitory activity with IC50 values of 13 and 22 nM for BD2 of BRD4 and JAK2, respectively. The western blot assay demonstrated that 9j performed good functional potency in the NF-κB pathway and the phosphorylation of p65, IκB-α, and IKKα/ß signal intensities were suppressed on RAW264.7 cell lines. Furthermore, 9j significantly improved the disease symptoms in a Ba/F3-JAK2V617F allograft model. Meanwhile, 9j was also effective in relieving symptoms in an acute ulcerative colitis model. Taken together, 9j was a potent JAK2/BRD4(BD2) dual target inhibitor and could be a potential lead compound in treating myeloproliferative neoplasms and inflammatory diseases.

Enhanced Interlayer Interaction and Second-Harmonic-Generation Response in a KBe2BO3F2-Type Inorganic-Organic Hybrid Zinc Borate.

A new inorganic-organic hybrid zinc borate was prepared under hydrothermal conditions. This compound is the first KBe2BO3F2 (KBBF) derivative with zinc borate layers linked by mononegatively charged amino acids. Notably, it exhibits a relatively large second-harmonic-generation response of about 2.0 times that of KBBF and a moderate birefringence for phase matching in the UV region. The enhanced interlayer interaction was evaluated by theoretical calculations based on density functional theory.

QM/MM investigation of the catalytic mechanism of processive endoglucanase Cel9G from Clostridium cellulovorans.

Carbohydrate degradation catalyzed by glucoside hydrolases (GHs) is a major mechanism in biomass conversion. GH family 9 endoglucanase (Cel9G) from Clostridium cellulovorans, a typical multimodular enzyme, contains a catalytic domain closely linked to a family 3c carbohydrate-binding module (CBM3c). Unlike the conventional behavior proposed for other carbohydrate-binding modules, CBM3c has a direct impact on catalytic activity. In this work, extensive molecular dynamics (MD) simulations were employed to clarify the functional role of CBM3c. Furthermore, the detailed catalytic mechanism of Cel9G was investigated at the atomistic level using the combined quantum mechanical and molecular mechanical (QM/MM) method. Based on these simulations, owing to the rigidity of the peptide linker, CBM3c may affect the enzymatic activity via direct interactions with alpha helix 4 of GH9, especially with the K123 and H125 residues. In addition, using cellohexaose as a substrate, the QM/MM MD simulations confirmed that this enzyme can cleave the ß-1,4-glycosidic linkage via an inverting mechanism. An oxocarbenium ion-like transition state was located with a barrier height of 19.6 kcal mol-1. Furthermore, the G(-1) pyranose unit preferentially adopted a distorted 1S5/4H5 conformer in the enzyme-substrate complex. For the cleavage of the glycosidic bond, we were able to identify a plausible route (1S5/4H5 → [4H5/4E]# → 4C1) from the reactant to the product at the G(-1) site.

Molecular dynamic simulation of prenucleation of apatite at a type I collagen template: ion association and mineralization control.

Biomineralization is a vital physiological process in living organisms, hence elucidating its mechanism is crucial in the optimization of controllable biomaterial preparation with hydroxyapatite and collagen, which could provide information for the design of innovative biomaterials. However, the mechanisms by which minerals and collagen interact in various ionic environments are unclear. Here, we applied molecular dynamics and free energy simulations to clarify type I collagen-mediated HAP prenucleation and simulated the physiological environment using different phosphate and carbonate protonation states. Calcium phosphate mineral formation on the type I collagen surface drastically differed among various H2PO4-, HPO42-, PO43-, CO32-, and HCO3- compositions. Our simulations indicated that the presence of HPO42- in the solution phase is critical to regulate the apatite nucleation, whereas the presence of H2PO4- may be inhibitory. The inclusion of CO32- in the solution might promote calcium phosphate cluster formation. In contrast, apatite cluster size may be regulated by changing the anion concentration ratios, including PO43-/HPO42- and PO43-/CO32-. Our free energy simulations attributed these phenomena to relative differences in binding thermostability and ion association kinetics. Our simulations provide a theoretical approach toward the effective control of collagen mineralization and the preparation of novel biomaterials.

Processive binding mechanism of Cel9G from Clostridium cellulovorans: molecular dynamics and free energy landscape investigations.

The degradation of recalcitrant polysaccharides such as cellulose and chitin requires the synergistic functionality of processive glycosidase (GH) cocktails. Understanding the fundamental phenomenon of processivity is of biological and economic importance for the conversion of biomass into biofuel. In this work, cellulase family 9 from Clostridium cellulovorans (Cel9G), which is a processive endoglucanase, was used to elucidate the processive binding mechanism with respect to polysaccharides, since it exhibits a multimodular crystallographic structure. Metadynamics and molecular dynamics simulations were performed to explore the dynamics of cellulose chain binding to Cel9G via processive motion. The processive movement of the cellulose chain towards the catalytic domain may exhibit several local minima, which are related to strong CH/π interactions between the sugar rings and the aromatic residues distributed at the active site. For the binding of the G6 and G12 molecules, the energy barriers were determined to be 4.8 and 7.4 kcal mol-1, respectively. Based on the site-directed mutagenesis simulations of Y520A, it was found that the existence of Y520 is critical for processive binding. It is likely that Y520 and H125/Y416 form two anchor points to facilitate processive binding to polysaccharides. More importantly, the straight-line morphology of the substrate could be observed after the formation of the so-called slide mode, which is different from the V-shaped Michaelis complex structure revealed by quantum mechanics/molecular mechanics simulations. This indicates that an additional step, namely, catalytic activation, probably exists between processive binding and the hydrolysis reaction. Finally, a four-step catalytic cycle was proposed for Cel9G. Our work provides novel molecular-level insights into the structure-function relationship for the processive enzyme Cel9G and should aid the development of improved GH cocktails for the efficient cleavage of glycosidic linkages.

Molecular investigations of the prenucleation mechanism of bone-like apatite assisted by type I collagen nanofibrils: insights into intrafibrillar mineralization.

Bone is a typical inorganic-organic composite material with a multilevel hierarchical organization. In the lowest level of bone tissue, inorganic minerals, which are mainly composed of hydroxyapatite, are mineralized within the type I collagen fibril scaffold. Understanding the crystal prenucleation mechanism and growth of the inorganic phase is particularly important in the design and development of materials with biomimetic nanostructures. In this study, we built an all-atom human type I collagen fibrillar model with a 67 nm overlap/gap D-periodicity. Arginine residues were shown to serve as the dominant cross-linker to stabilize the fibril scaffold. Subsequently, the prenucleation mechanism of collagen intrafibrillar mineralization was investigated using a molecular dynamics approach. Considering the physiological pH of the human body (i.e., ∼7.4), HPO42- was initially used to simulate the protonation state of the phosphate ions. Due to the spatially constrained effects resulting from the overlap/gap structure of the collagen fibrils, calcium phosphate clusters formed mainly inside the hole zone but with different spatial distributions along the long axis direction; this indicated that the nucleation of calcium phosphate may be highly site-selective. Furthermore, the model containing both HPO42- and PO43- in the solution phase formed significantly larger clusters without any change in the nucleation sites. This phenomenon suggests that the existence of PO43- is beneficial for the mineralization process, and so the conversion of HPO42- to PO43- was considered a critical step during mineralization. Finally, we summarize the nucleation mechanism for collagen intrafibrillar mineralization, which could contribute to the fabrication of mineralized collagen biomimetic materials.

The binding mechanism of NHWD-870 to bromodomain-containing protein 4 based on molecular dynamics simulations and free energy calculation.

Bromodomain and extra-terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are epigenetic readers with tandem bromodomains. Small-molecule inhibitors of BET proteins are a promising treatment strategy against cancer. For example, NHWD-870 can inhibit BRD4 (BD1 + BD2). Presently, structural data on NHWD-870 bound BRD4 remain lacking. Herein, we investigate the interactions between NHWD-870 and BRD4 (BD1 and BD2) via molecular docking, molecular dynamics simulation, and binding free energy calculations. NHWD-870 showed a similar binding affinity for BD1 and BD2 of BRD4. Binding free energy calculations for the R/S conformations of NHWD-870 suggest that the chiral centre of NHWD-870 may confer similar roles upon the R and S conformations for binding with BRD4, facilitating the identification of novel BRD4 inhibitors.

Exploring the stability of inhibitor binding to SIK2 using molecular dynamics simulation and binding free energy calculation.

Salt inducible kinase 2 (SIK2) is a calcium/calmodulin-dependent protein kinase-like kinase that is implicated in a variety of biological phenomena, including cellular metabolism, growth, and apoptosis. SIK2 is the key target for various cancers, including ovarian, breast, prostate, and lung cancers. Although potent inhibitors of SIK2 are being developed, their binding stability and functional role are not presently known. In this work, we studied the detailed interactions between SIK2 and four of its inhibitors, HG-9-91-01, KIN112, MRT67307, and MRT199665, using molecular docking, molecular dynamics simulation, binding free energy calculation, and interaction fingerprint analysis. Intermolecular interactions revealed that HG-9-91-01 and KIN112 have stronger interactions with SIK2 than those of MRT199665 and MRT67307. The key residues involved in binding with SIK2 are conserved among all four inhibitors. Our results explain the detailed interaction of SIK2 with its inhibitors at the molecular level, thus paving the way for the development of targeted efficient anti-cancer drugs.

Two Copper-Rich Open-Framework Chalcogenides Built from Unusual [Cu5(SnxM1-x)Se10] Clusters and [(SnxM1-x)2Se6] Dimeric Linkers (M = In and Ga).

Reported here are two unprecedented copper-rich open-framework chalcogenides constructed from unusual [Cu5(SnxM1-x)Se10] clusters and [(SnxM1-x)2Se6] dimeric linkers (M = In and Ga). The photoresponsive properties in the IR range and the photocatalytic activity for degradation of methylene blue dye of these two isostructural semiconductors were proved to be effectively adjusted by trivalent metal ions in a cluster.

Molecular docking and molecular dynamics simulation studies on the adsorption/desorption behavior of bone morphogenetic protein-7 on the ß-tricalcium phosphate surface.

The adsorption/desorption behavior, and conformational and orientational changes of proteins on the surface of biomaterials are significant parameters for understanding how biomaterials perform their biological functions. In this study, for the first time, the interactions between BMP-7 and ß-TCP (001) surface models with different ion-rich terminations (Ca-rich and P-rich) were investigated by molecular dynamics simulation (MD) and steered molecular dynamics simulation (SMD). The results indicated that BMP-7 preferentially interacts with both Ca-rich and P-rich ß-TCP (001) surfaces at its wrist epitope residues with certain conformational changes, which led to more exposure of BMP-7 knuckle epitope residues to the environment and facilitation for binding to the type II receptor. Compared to the P-rich surface, it is speculated that the Ca-rich surface was more conducive to BMP-7 signal transduction since the upright orientation of the protein adsorption would lead to smaller hindrance for receptor binding. This study provided more atomistic and molecular information for better understanding the process of Ca-P surfaces affecting BMP-7 biological properties and further interpreted the osteoinductive mechanism from the perspective of growth factor adsorption. Moreover, the docking screening method adopted in this study is of guiding significance to the design and development of bioactive materials.

Molecular dynamics investigations of oligosaccharides recognized by family 16 and 22 carbohydrate binding modules.

As a non-catalytic domain, carbohydrate binding modules (CBMs) are often considered to play some key roles in the degradation and recognition of polysaccharides catalyzed by cellulases. In this work, we investigated the recognition dynamics of cello- or xylo-saccharides by two typical CBMs (CBM16-1 and CBM22-2), which are grouped into Type B CBMs. By combining extensive molecular dynamics, principle component analysis, and binding free energy calculations, we constructed several complex models of the two CBMs in both complex cello- and xylo-oligosaccharides. The corresponding substrate recognition affinity and critical residues having significant contributions were systematically investigated. The residues containing aromatic side chain groups were shown to contribute significantly to substrate binding. The calculated binding free energies were in fairly good agreement with the experimental measurements with the absolute mean error of 0.69 kcal mol-1. The overall electrostatic interactions were shown to have negative effects on substrate recognition. Further metadynamics simulations revealed the substrate dissociation process.

Insights into the biotransformation of 2,4,6-trinitrotoluene by the old yellow enzyme family of flavoproteins. A computational study.

Biodegradation is a cost-effective and environmentally friendly alternative to removing 2,4,6-trinitrotoluene (TNT) pollution. However, mechanisms of TNT biodegradation have been elusive. To enhance the understanding of TNT biotransformation by the Old Yellow Enzyme (OYE) family, we investigated the crucial first-step hydrogen-transfer reaction by molecular dynamics simulations, docking technologies and empirical valence bond calculations. We revealed the significance of the π-π stacking conformation between the substrate TNT and the reduced flavin mononucleotide (FMNH2) cofactor, which is a prerequisite for the aromatic ring reduction of TNT. Under the π-π stacking conformation, the barrier of the hydrogen-transfer reaction in the aromatic ring reduction is about 16 kcal mol-1 lower than that of nitro group reduction. Then, we confirmed the mechanism of controlling the π-π stacking, that is, the π-π interaction competition mechanism. It indicates that the π-π stacking of TNT and FMNH2 occurs only when the π-π interaction between FMNH2 and TNT is stronger than that between TNT and several key residues with aromatic rings. Finally, based on the competition mechanism, the formation of π-π stacking of TNT and FMNH2 can be successfully enabled by removing the aromatic ring of those key residues in enzymes that originally only transform TNT through the nitro group reduction. This testified the validity of the π-π interaction competition mechanism. This work theoretically clarifies the molecular mechanism of the first-step hydrogen-transfer reaction for the biotransformation of TNT by the OYE family. It is helpful to obtain the enzymes that can biodegrade TNT through the aromatic ring reduction.

Mechanism of Direct C-H Arylation of Pyridine via a Transient Activator Strategy: A Combined Computational and Experimental Study.

Recently, we realized the highly selective one-pot synthesis of 2,6-diarylpyridines by using a Pd-catalyzed direct C-H arylation approach via a transient activator strategy. Although methylation reagent as a transient activator and Cu(I) salt or oxide were found to be prerequisites, details regarding the mechanism remained unclear. In this paper, DFT calculations combined with experimental investigations were carried out to elucidate the principle features of this transformation. The results reveal (1) the origin of the exquisite diarylating selectivity of the pyridine under the transient strategy; (2) the possible demethylating reagent as the counteranion of the pyridinium salt; (3) the reason why Cu2O is a better Cu(I) resource than others.

Molecular dynamics investigations of cello-oligosaccharide recognition by Cel9G-CBM3c from Clostridium cellulovorans.

The processive mechanism of cellulases against cellulose represents one of the key mechanisms in the conversion of biomass. A reliable model of substrate binding in a multidomain cellulase is a prerequisite for fully understanding this mechanism. In this study, the specificity of the recognition of the polysaccharide by the multidomain endoglucanase Cel9G from Clostridium cellulovorans was investigated by molecular dynamics simulations. Aromatic ring-containing residues were found to be critical for stabilizing the substrate. The calculated subtotal contributions of polar residues close to the active site, e.g., D58, E244, R315 and D420, also have some critical functions in substrate binding. Unlike other members of the carbohydrate-binding module family, CBM3c alone is shown not to bind cellulose very well, which is also consistent with experimental conclusions.

Understanding the hydrogen transfer mechanism for the biodegradation of 2,4,6-trinitrotoluene catalyzed by pentaerythritol tetranitrate reductase: molecular dynamics simulations.

The explosive 2,4,6-trinitrotoluene (TNT) is a highly toxic pollutant. Biodegradation is inevitably one of the most cost-effective and enviromentally friendly means of removing TNT pollution. However, the aromatic derivatives from the reduction of nitro groups by several classic enzymes are still toxic. Besides the reduction of nitro groups, pentaerythritol tetranitrate reductase (PETNR) offers a potential route to ring fission and complete degradation of TNT through the pathway of the Meisenheimer complex. This work is devoted to deeply understand the essence of the Meisenheimer pathway and mainly focus on the crucial hydrogen-transfer reaction by means of molecular dynamics (MD) simulations. We obtain three valuable findings. Firstly, the parallel π-π stacking between TNT and the flavin mononucleotide (FMN) cofactor is a precondition. The key residue controlling this conformation is His181. Although His184 does not interact with TNT, the mutation from His184 to Asn184 would abolish the π-π structure. Secondly, the data of the empirical valence bond (EVB) show that the Meisenheimer pathway is predominant because its activation barrier is 6.7 kcal mol-1 far less than that of nitro reduction (26.6 kcal mol-1). Finally, based on the results of thermodynamic integration (TI), the type of transferred hydrogen is also ensured, that is, the H anion (H-) for the Meisenheimer complex and the H radical (H˙) for nitro reduction. Our findings provide an exhaustive understanding for the first hydrogen transfer reaction that has a decisive effect on two competing pathways, and help in searching for and designing new enzymes that can effectively degrade TNT.

A 36-Membered Ring Metal Chalcogenide with a Very Low Framework Density.

Reported here is a new open-framework metal chalcogenide containing extra-large 36-ring channels. This compound has a 3-connected etc topology by regarding supertetrahedral T2 clusters as the structural nodes. It has a very low framework density (3.4 tetrahedra per 1000 Å3) with each framework cation participating in three 3-rings. The organic cations within its intersecting channels can be partially exchanged out by Cs+ ions with the preservation of its framework structure.