Mechanism and origin of enantioselectivity for organocatalyzed asymmetric heteroannulation of alkynes in the construction of axially chiral C2-arylquinoline.

Axially chiral C2-arylquinoline has been successfully constructed via asymmetric heteroannulation of alkynes catalyzed by chiral phosphoric acid with high yield and high enantioselectivity. Inspired by this intriguing work, theoretical calculations have been carried out, and the detailed reaction mechanism has been elaborated, in which the whole reaction can be divided into steps including hydrogen transfer, C-N bonding, annulation reaction and the final dehydration processes. The initial hydrogen-transfer reaction has two possible pathways, while the subsequent C-N bonding process has eight possible pathways. Then, after the annulation reaction and the final dehydration processes, the major product and byproduct were formed. QTAIM and IGMH analyses were used to illustrate the role of weak intermolecular interactions in the catalytic process, and the distortion/interaction and EDA analyses provided a deeper understanding of the origin of enantioselectivity. The calculated results are consistent with the experimental results. This work would provide valuable insights into asymmetric reactions catalyzed by chiral phosphoric acid.

Adsorption Behaviors of Typical Proteins on BP, GR, and C2N Surfaces.

The biotoxicity of nanomaterials is very important for the application of nanomaterials in biomedical systems. In this study, proteins with varying secondary structures (α-helices, ß-sheets, and mixed α/ß structures) were employed to investigate the biological properties of three representative two-dimensional (2D) nanomaterials; these nanomaterials consisted of black phosphorus (BP), graphene (GR), and nitrogenized graphene (C2N) and were studied using molecular dynamics simulations. The results showed that the α-helix motif underwent a slight structural change on the BP surface and little structural change on the C2N surface. In contrast, the structure of the ß-sheet motif remained fairly intact on both the BP and C2N surfaces. The α-helix and ß-sheet motifs were able to freely migrate on the BP surface, but they were anchored to the C2N surface. In contrast to BP and C2N, GR severely disrupted the structures of the α-helix and ß-sheet motifs. BBA protein with mixed α/ß structures adsorbed on the BP and C2N surfaces and exhibited biological behaviors that were consistent with those of the α-helix and ß-sheet motifs. In summary, C2N may possess better biocompatibility than BP and GR and is expected to have applications in the biomedical field. This study not only comprehensively evaluated the biological characteristics of nanomaterials but also provided a theoretical strategy to explore and distinguish the surface characteristics of nanomaterials.

Molecular modeling study on the dynamical structural features of human smoothened receptor and binding mechanism of antagonist LY2940680 by metadynamics simulation and free energy calculation.

BACKGROUND: The smoothened (SMO) receptor, one of the Class F G protein coupled receptors (GPCRs), is an essential component of the canonical hedgehog signaling pathway which plays a key role in the regulation of embryonic development in animals. The function of the SMO receptor can be modulated by small-molecule agonists and antagonists, some of which are potential antitumour agents. Understanding the binding mode of an antagonist in the SMO receptor is crucial for the rational design of new antitumour agents. METHODS: Molecular dynamics (MD) simulation and dynamical network analysis are used to study the dynamical structural features of SMO receptor. Metadynamics simulation and free energy calculation are employed to explore the binding mechanism between the antagonist and SMO receptor. RESULTS: The MD simulation results and dynamical network analysis show that the conserved KTXXXW motif in helix VIII has strong interaction with helix I. The α-helical extension of transmembrane 6 (TM6) is detected as part of the ligand-binding pocket and dissociation pathway of the antagonist. The metadynamics simulation results illustrate the binding mechanism of the antagonist in the pocket of SMO receptor, and free energy calculation shows the antagonist needs to overcome about 38kcal/mol of energy barrier to leave the binding pocket of SMO receptor. CONCLUSIONS: The unusually long TM6 plays an important role on the binding behavior of the antagonist in the pocket of SMO receptor. GENERAL SIGNIFICANCE: The results can not only profile the binding mechanism between the antagonist and Class F GPCRs, but also supply the useful information for the rational design of a more potential small molecule antagonist bound to SMO receptor.

In Silico Identification of Protein S-Palmitoylation Sites and Their Involvement in Human Inherited Disease.

S-Palmitoylation is a key regulatory mechanism controlling protein targeting, localization, stability, and activity. Since increasing evidence shows that its disruption is implicated in many human diseases, the identification of palmitoylation sites is attracting more attention. However, the computational methods that are published so far for this purpose have suffered from a poor balance of sensitivity and specificity; hence, it is difficult to get a good generalized prediction ability on an external validation set, which holds back the further analysis of associations between disruption of palmitoylation and human inherited diseases. In this work, we present a reliable identification method for protein S-palmitoylation sites, called SeqPalm, based on a series of newly composed features from protein sequences and the synthetic minority oversampling technique. With only 16 extracted key features, this approach achieves the most favorable prediction performance up to now with sensitivity, specificity, and Matthew's correlation coefficient values of 95.4%, 96.3%, and 0.917, respectively. Then, all known disease-associated variations are studied by SeqPalm. It is found that 243 potential loss or gain of palmitoylation sites are highly associated with human inherited disease. The analysis presents several potential therapeutic targets for inherited diseases associated with loss or gain of palmitoylation function. There are even biological evidence that are coordinate with our prediction results. Therefore, this work presents a novel approach to discover the molecular basis of pathogenesis associated with abnormal palmitoylation. SeqPalm is now available online at http://lishuyan.lzu.edu.cn/seqpalm , which can not only annotate the palmitoylation sites of proteins but also distinguish loss or gain of palmitoylation sites by protein variations.

Comparative Simulative Analysis and Design of Single-Chain Self-Assembled Protein Cages.

Coiled-coil protein origami (CCPO) is a modular strategy for the de novo design of polypeptide nanostructures. It represents a type of modular design based on pairwise-interacting coiled-coil (CC) units with a single-chain protein programmed to fold into a polyhedral cage. However, the mechanisms underlying the self-assembly of the protein tetrahedron are still not fully understood. In the present study, 18 CCPO cages with three different topologies were modeled in silico. Then, molecular dynamics simulations and CC parameters were calculated to characterize the dynamic properties of protein tetrahedral cages at both the local and global levels. Furthermore, a deformed CC unit was redesigned, and the stability of the new cage was significantly improved.

Fixed-component lanthanide-hybrid-fabricated full-color photoluminescent films as vapoluminescent sensors.

Full-color lanthanide (Ln) photoluminescent materials have attracted considerable interest owing to their potential applications in display systems and lighting technologies. Herein, full-color photoluminescent films have been designed and fabricated facilely with a fixed-component Ln-based (Ln=Tb and Eu) polymer hybrid doped with a proton-sensitive amide-type ß-diketonated photosensitizer, N-(2-pyridinyl)benzoylacetamide (HPBA). The tunable photoluminescence emissions of the films are achieved by changing the amounts of OH(-) in the hybrid rather than varying the relative concentrations of the lanthanide ions and photosensitizers, thus representing a new paradigm for full-color displays. The emission color can also be finely tuned through the variation of the excitation wavelength, and white-light emission can be achieved when the given film is excited at the visible region (405 nm). The photophysical properties and the mechanisms of the intra- and intermolecular energy transfer before and after deprotonation have been investigated in detail. Meanwhile, the films might find application as vapoluminescent sensors due to their good stability, sensitivity, reversibility, and quick response when triggered by a base-acid vapor.

The role of the conjugate bridge in electronic structures and related properties of tetrahydroquinoline for dye sensitized solar cells.

To understand the role of the conjugate bridge in modifying the properties of organic dye sensitizers in solar cells, the computations of the geometries and electronic structures for 10 kinds of tetrahydroquinoline dyes were performed using density functional theory (DFT), and the electronic absorption and fluorescence properties were investigated via time dependent DFT. The population analysis, molecular orbital energies, radiative lifetimes, exciton binding energies (EBE), and light harvesting efficiencies (LHE), as well as the free energy changes of electron injection ( ) and dye regeneration ( ) were also addressed. The correlation of charge populations and experimental open-circuit voltage (Voc) indicates that more charges populated in acceptor groups correspond to larger Voc. The elongating of conjugate bridge by thiophene units generates the larger oscillator strength, higher LHE, larger absolute value of , and longer relative radiative lifetime, but it induces the decreasing of EBE and . So the extending of conjugate bridge with thiopene units in organic dye is an effective way to increase the harvest of solar light, and it is also favorable for electron injection due to their larger . While the inversely correlated relationship between EBE and LHE implies that the dyes with lower EBE produce more efficient light harvesting.

Understanding the electronic structures and absorption properties of porphyrin sensitizers YD2 and YD2-o-C8 for dye-sensitized solar cells.

The electronic structures and excitation properties of dye sensitizers determine the photon-to-current conversion efficiency of dye sensitized solar cells (DSSCs). In order to understand the different performance of porphyrin dye sensitizers YD2 and YD2-o-C8 in DSSC, their geometries and electronic structures have been studied using density functional theory (DFT), and the electronic absorption properties have been investigated via time-dependent DFT (TDDFT) with polarizable continuum model for solvent effects. The geometrical parameters indicate that YD2 and YD2-o-C8 have similar conjugate length and charge transfer (CT) distance. According to the experimental spectra, the HSE06 functional in TDDFT is the most suitable functional for describing the Q and B absorption bands of porphyrins. The transition configurations and molecular orbital analysis suggest that the diarylamino groups are major chromophores for effective CT excitations (ECTE), and therefore act as electron donor in photon-induced electron injection in DSSCs. The analysis of excited states properties and the free energy changes for electron injection support that the better performance of YD2-o-C8 in DSSCs result from the more excited states with ECTE character and the larger absolute value of free energy change for electron injection.

Quantification of hyperconjugative effect on the proton donor X-H bond length changes in the red- and blueshifted hydrogen-bonded complexes.

A whole dataset containing 55 hydrogen bonds were studied at the MP2/aug-cc-pVTZ level of theory. The changes of geometries and stretching vibrational frequencies show that there are 31 redshifted and 24 blueshifted hydrogen-bonded complexes. Natural bond orbital analysis was carried out at the B3LYP/aug-cc-pVTZ level of theory to obtain the electron densities in the bonding and antibonding orbitals of the proton donor X-H bond, which are closely associated with its bond length. Based on their relationship, a generally applicable method considering both the electron densities in the bonding and antibonding orbitals of the proton donor X-H bond has been developed to quantitatively describe the hyperconjugative effect on the X-H bond length changes in these hydrogen-bonded complexes.

Comparative antibacterial analysis of the anthraquinone compounds based on the AIM theory, molecular docking, and dynamics simulation analysis.

BACKGROUND: Hydroxyanthraquinones and anthraquinone glucoside derivatives are always considered as the active antibacterial components. METHODS: Comparison of structure characteristics and antibacterial effect of these compounds was performed by applying quantum chemical calculations, atoms in molecules theory, molecular docking, and dynamics simulation procedure. Density functional theory calculation with B3LYP using 6-31G (d, p) basis set has been used to determine ground state molecular geometries. RESULTS: The molecular geometric stability, electrostatic potential, frontier orbital energies, and topological properties were analyzed at the active site. Once glucose ring is introduced into the hydroxyanthraquinone rings, almost all of the positive molecular potentials are distributed among the hydroxyl hydrogen atoms of the glucose rings. In addition, low electron density ρ (r) and positive Laplacian value of the O-H bond of the anthraquinone glucoside are the evidences of the highly polarized and covalently decreased bonding interactions. The anthraquinone glucoside compounds have generally higher intermolecular binding energies than the corresponding aglycones due to the strong interaction between the glucose rings and the surrounding amino acids. Molecular dynamics simulations further explored the stability and dynamic behavior of the anthraquinone compound and protein complexes through RMSD, RMSF, SASA, and Rg. CONCLUSION: The type of carboxyl, hydroxyl, and hydroxymethyl groups on phenyl ring and the substituent glucose rings is important to the interactions with the topoisomerase type II enzyme DNA gyrase B.

First-principles calculations of high-pressure physical properties anisotropy for magnesite.

The first-principles calculations based on density functional theory with projector-augmented wave are used to study the anisotropy of elastic modulus, mechanical hardness, minimum thermal conductivity, acoustic velocity and thermal expansion of magnesite (MgCO3) under deep mantle pressure. The calculation results of the phase transition pressure, equation of state, elastic constants, elastic moduli, elastic wave velocities and thermal expansion coefficient are consistent with those determined experimentally. The research results show that the elastic moduli have strong anisotropy, the mechanical hardness gradually softens with increasing pressure, the conduction velocity of heat in the [100] direction is faster than that in the [001] direction, the plane wave velocity anisotropy first increases and then gradually decreases with increasing pressure, and the shear wave velocity anisotropy increases with the increase of pressure, the thermal expansion in the [100] direction is greater than that in the [001] direction. The research results are of great significance to people's understanding of the high-pressure physical properties of carbonates in the deep mantle.

Halogen as halogen-bonding donor and hydrogen-bonding acceptor simultaneously in ring-shaped H3N·X(Y)·HF (X = Cl, Br and Y = F, Cl, Br) complexes.

A series of ring-shaped molecular complexes formed by H(3)N, HF and XY (X = Cl, Br and Y = F, Cl, Br) have been investigated at the MP2/aug-cc-pVTZ level of theory. Their optimized geometry, stretching mode, and interaction energy have been obtained. We found that each complex possesses two red-shifted hydrogen bonds and one red-shifted halogen bond, and the two hydrogen bonds exhibit strong cooperative effects on the halogen bond. The cooperativity among the NH(3)···FH, FH···XY and H(3)N···XY interactions leads to the formations of these complexes. The AIM analysis has been performed at the CCSD(T)/aug-cc-pVQZ level of theory to examine the topological characteristics at the bond critical point and at the ring critical point, confirming the coexistence of the two hydrogen bonds and one halogen bond for each complex. The NBO analysis carried out at the B3LYP/aug-cc-pVTZ level of theory demonstrates the effects of hyperconjugation, hybridization, and polarization coming into play during the hydrogen and halogen bonding formations processes, based on which a clockwise loop of charge transfer was discovered. The molecular electrostatic potential has been employed to explore the formation mechanisms of these molecular complexes.

Study on novel PtNP-sorafenib and its interaction with VEGFR2.

With the developments of nanodrugs, some drugs have combined with nanoparticles (NPs) to reduce their side-effects and increase their therapeutic activities. Here, a novel nanodrug platinum nanoparticle-sorafenib (PtNP-SOR) was proposed for the first time. By means of molecular dynamics simulation, the stability and biocompatibility of PtNP-SOR were investigated. Then, the interaction mechanism between PtNP-SOR and vascular endothelial growth factor receptor 2 (VEGFR2) was explored and compared with that of the peptide 2a coated PtNPs. The results showed that PtNP-SOR could bind to VEGFR2 more stably, which was driven by the Coulombic and strong dispersion interaction between PtNP-SOR and VEGFR2. According to their contributions obtained from the decomposition of binding free energies, the key residues in VEGFR2 were identified to form the specific space, which increased the affinity with PtNP-SOR. This study provided useful insights to the design of PtNP-drugs as well as important theoretical proofs to the interaction between PtNP-SOR and VEGFR2 at a molecular level, which can be of large help during the development and optimization of novel nanodrugs.

Effects of Hydroxyl Group on the Interaction of Carboxylated Flavonoid Derivatives with S. Cerevisiae α-Glucosidase.

INTRODUCTION: Carboxyalkyl flavonoids derivatives are considered as effective inhibitors in reducing post-prandial hyperglycaemia. METHODS: Combined with Density Functional Theory (DFT) and the theory of Atoms in Molecules (AIM), molecular docking and charge density analysis are carried out to understand the molecular flexibility, charge density distribution and the electrostatic properties of these carboxyalkyl derivatives. RESULTS: Results show that the electron density of the chemical bond C14-O17 on B ring of molecule II increases while O17-H18 decreases at the active site, suggesting the existence of weak noncovalent interactions, most prominent of which are H-bonding and electrostatic interaction. When hydroxyl groups are introduced, the highest positive electrostatic potentials are distributed near the B ring hydroxyl hydrogen atom and the carboxyl hydrogen atom on the A ring. It was reported that quercetin has a considerably inhibitory activity to S. cerevisiae α-glucosidase, from the binding affinities, it is suggested that the position and number of hydroxyl groups on the B and C rings are also pivotal to the hypoglycemic activity when the long carboxyalkyl group is introduced into the A ring. CONCLUSION: It is concluded that the presence of three well-defined zones in the structure, both hydrophobicity alkyl, hydrophilicity carboxyl and hydroxyl groups are necessary.

Is Crocin a Potential Anti-tumor Candidate Targeting Microtubules? Computational Insights From Molecular Docking and Dynamics Simulations.

Although it is known crocin, a hydrophilic compound from the herbal plant Crocus sativus L., has promising antitumor activity, the detailed mechanism of its antitumor activity was not well understood. Recent experiments suggested tubulin as the primary target for the antitumor activity of crocin. However, due to a lack of crystal structure of tubulin bound with crocin, the exact binding mode and interaction between crocin and tubulin remains exclusive. In the present work, a computational study by integrating multiple conformation docking, molecular dynamics simulation as well as residue interaction network analysis was performed to investigate the molecular mechanism of crocin-tubulin interaction. By comparing the docking score, the most likely binding mode CRO_E1 were identified from 20 different binding modes of crocin in the vinca binding pockets. Further molecular dynamics simulation of CRO_E1 complex showed the binding of crocin is more stable than the inhibitor soblidotin and vinblastine. During the simulation course, an excessive number of hydrogen bonds were observed for the ligand crocin. The binding free energy of crocin-tubulin complex was calculated as -79.25 ± 7.24 kcal/mol, which is almost twice of the ligand soblidotin and vinblastine. By using energy decomposition, hot residues for CRO_E1 were identified as Gln11, Gln15, Thr72, Ser75, Pro173-Lys174-Val175-Ser176-Asp177, Tyr222, and Asn226 in the ß-chain, and Asp245, Ala247-Leu248, Val250, Asn329, and Ile332 in the α-chain. Residue interaction network analysis also showed the importance of these hot residues in the interaction network of crocin-tubulin complex. In addition, a common residue motif Val175-Xxx176-Asp177 was discovered for all three bindings, suggesting its importance in future drug design. The study could provide valuable insights into the interaction between crocin and tubulin, and give suggestive clues for further experimental studies.

Two novel self-assemblies of supramolecular solar cells using N-heterocyclic-anchoring porphyrins.

Two novel N-substituted anchoring porphyrins (ZnPAtz and ZnPAim) have been devised and synthesized. Moreover, these two anchoring porphyrins were linked to the TiO2 semiconductor through carboxyl groups and then a zinc porphyrin ZnP was bound to the anchoring porphyrin using a zinc-to-ligand axial coordination approach. The different performances of these assemblies were compared with single anchoring porphyrin devices ZnPAtz and ZnPAim. The photoelectric conversion efficiency of the new supramolecular solar cells sensitized by ZnP-ZnPAx (x=tz, im) has been improved. The ZnP-ZnPAtz-based DSSCs provided the highest photovoltaic efficiency (1.86%). Fundamental studies showed that incorporation of these assemblies promote light-harvesting efficiency.

A Universal Strategy To Prepare Sulfur-Containing Polymer Composites with Desired Morphologies for Lithium-Sulfur Batteries.

Lithium-sulfur (Li-S) batteries are probably the most promising candidates for the next-generation batteries owing to their high energy density. However, Li-S batteries face severe technical problems where the dissolution of intermediate polysulfides is the biggest problem because it leads to the degradation of the cathode and the lithium anode, and finally the fast capacity decay. Compared with the composites of elemental sulfur and other matrices, sulfur-containing polymers (SCPs) have strong chemical bonds to sulfur and therefore show low dissolution of polysulfides. Unfortunately, most SCPs have very low electron conductivity and their morphologies can hardly be controlled, which undoubtedly depress the battery performances of SCPs. To overcome these two weaknesses of SCPs, a new strategy was developed for preparing SCP composites with enhanced conductivity and desired morphologies. With this strategy, macroporous SCP composites were successfully prepared from hierarchical porous carbon. The composites displayed discharge/charge capacities up to 1218/1139, 949/922, and 796/785 mA h g-1 at the current rates of 5, 10, and 15 C, respectively. Considering the universality of this strategy and the numerous morphologies of carbon materials, this strategy opens many opportunities for making carbon/SCP composites with novel morphologies.

The electronic structure engineering of organic dye sensitizers for solar cells: The case of JK derivatives.

The design and development of novel dye sensitizers are effective method to improve the performance of dye-sensitized solar cells (DSSCs) because dye sensitizers have significant influence on photo-to-current conversion efficiency. In the procedure of dye sensitizer design, it is very important to understand how to tune their electronic structures and related properties through the substitution of electronic donors, acceptors, and conjugated bridges in dye sensitizers. Here, the electronic structures and excited-state properties of organic JK dye sensitizers are calculated by using density functional theory (DFT) and time dependent DFT methods. Based upon the calculated results, we investigated the role of different electronic donors, acceptors, and π-conjugated bridges in the modification of electronic structures, absorption properties, as well as the free energy variations for electron injection and dye regeneration. In terms of the analysis of transition configurations and molecular orbitals, the effective chromophores which are favorable for electron injection in DSSCs are addressed. Meanwhile, considering the absorption spectra and free energy variation, the promising electronic donors, π-conjugated bridges, and acceptors are presented to design dye sensitizers.

Understanding the drug resistance mechanism of hepatitis C virus NS5B to PF-00868554 due to mutations of the 423 site: a computational study.

NS5B, a hepatitis C virus (HCV) RNA-dependent RNA polymerase (RdRp) that plays a key role in viral replication, is an important target in the discovery of antiviral agents. PF-00868554 is a potent non-nucleoside inhibitor (NNI) that binds to the Thumb II allosteric pocket of NS5B polymerase and has shown significant promise in phase II clinical trials. Unfortunately, several PF-00868554 resistant mutants have been identified. M423 variants were the most common NS5B mutations that occurred after PF-00868554 monotherapy. In this study, we used molecular dynamics (MD) simulations, binding free energy calculations and free energy decomposition to explore the drug resistance mechanism of HCV to PF-00868554 resulting from three representative mutations (M423T/V/I) in NS5B polymerase. Free energy decomposition analysis reveals that the loss of binding affinity mainly comes from the reduction of both van der Waals (ΔE(vdw)) and electrostatic interaction contributions in the gas phase (ΔE(ele)). Further structural analysis indicates that the location of PF-00868554 and the binding mode changed due to mutation of the residue at the 423 site of NS5B polymerase from methionine to threonine, isoleucine or valine, which further resulted in the loss of binding ability of PF-00868554 to NS5B polymerase. The obtained computational results will have important value for the rational design of novel non-nucleoside inhibitors targeting HCV NS5B polymerase.

The role of Cys179-Cys214 disulfide bond in the stability and folding of prion protein: insights from molecular dynamics simulations.

Prion diseases are associated with misfolding and aggregation of prion protein (PrP). Cellular prion protein contains a disulfide bond linking Cys residues at positions 179 and 214. It has been proposed that this disulfide bond plays an important role in the conversion between cellular (PrP(C)) and the scrapie form of prion protein (PrP(Sc)). To probe the role of this disulfide bond in the stability and folding of prion protein, we employed molecular dynamics simulations to study the reduced prion protein and a variant of PrP in which the two cysteines were replaced by alanines residues. The simulations highlighted the changes that occurred upon breakage of the disulfide bond. Breakage of the disulfide bond resulted in a shift of H1, elongation of the native ß-sheet and perturbation of the hydrophobic core of huPrP. The changes are similar to the conformational transitions of prion protein in low pH, in denaturing conditions or with pathogenic mutations, which indicate that rupture of the disulfide bond may lead to the misfolding of prion protein.