Ketoprofen (KP) is one of the most popular nonsteroidal anti-inflammatory drugs; however, drug-induced photosensitivity of KP has been reported as a serious adverse effect. KP incorporated into a protein can produce an allergen under UV irradiation, which causes drug-induced photosensitivity. The photochemistry of KP with 20 kinds of proteinogenic amino acids in phosphate buffer solutions at pH 7.4 was studied by transient absorption spectroscopy. The KP carboxylate anion (KP-) gave rise to a carbanion via a decarboxylation within a laser pulse, and the carbanion yielded 3-ethylbenzophenone ketyl biradical (3-EBPH) through a proton transfer reaction. Twelve kinds of proteinogenic amino acids obviously accelerated the reaction. Structural information on the complexes of KP docked in the binding sites of human serum albumin (HSA) was obtained by molecular mechanics (MM) and molecular dynamics (MD) calculations. The photochemical reaction of KP- with amino acid residues in HSA was discussed on the basis of the experimental and calculational results. The information on the reactivity of KP with the amino acids and the stable structures of the KP-HSA complexes should be essential for understanding of the initial step for drug-induced photosensitivity.

Microwave heating is widely used to accelerate organic reactions in the chemistry field. However, the effect of microwaves on chemical reaction has not yet been well characterized at the molecular level. In this review chapter, microwave heating processes of liquid crystals and an ethanol-hexane mixed solution under microwave irradiation were experimentally and theoretically investigated using in situ microwave irradiation nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulation, respectively. The temperature of the solution under microwave irradiation was estimated from a chemical shift calibrated temperature (CSC-temperature) which was determined from the temperature dependence of the 1H chemical shift. The CSC-temperatures of CH2 and CH3 non-polar protons of ethanol reflect the bulk temperature of a solution by the thermal microwave effect. The lower CSC-temperature of the OH polar protons in ethanol and much higher CSC-temperature of H-C=N (7′) and CH3-O (α’) protons of N-(4-methoxybenzyliden)-4-butylaniline with respect to the bulk temperature are attributed to the non-thermal microwave effects. According to the MD simulation under microwave irradiation, the number of hydrogen bonds increased in the ethanol-hexane mixed solution as a result of a non-thermal microwave effect. It is concluded that a coherently ordered low entropy state of polar molecules is induced by a non-thermal microwave effect. The ordered state induces molecular interaction, which may accelerate the chemical reaction rate between molecules with polar groups.

β-1,4-glucosaminoglucan (GG) was prepared from the sheath of a sulfur-oxidizing bacterium Thiothrix nivea. Recently, GG was found to be adsorbed by cellulose (paper) and is therefore potentially applicable as an aminating agent for cellulose. We attempted to increase the yield of GG using a fed-batch cultivation method. Furthermore, the behavior of GG molecules in water was theoretically and experimentally investigated. NMR analysis in combination with molecular dynamics calculation suggested that GG molecules tend to form soluble aggregates in water. It was experimentally revealed that the self-aggregation is enhanced by the addition of NaCl and reduced temperature. Adsorption of GG onto cellulose via hydrogen bonding was confirmed by molecular dynamics simulation. Adsorption was also promoted in the presence of NaCl but was inhibited by a reduction in temperature. Only 11% of the amino groups in the GG-treated paper was reactive, suggesting that GG molecules adsorbed by the paper were forming aggregates.

The waste valorization of spent coffee grounds (SCGs), which are obtainable in large amounts worldwide for new non-wood source has been considered. Cellulose nanofibers derived from SCGs have been successfully produced by 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO)-mediated oxidation of SCGs containing 10% cellulose (dry weight). The TEMPO-oxidized cellulose nanofibers (TOCNFs) are 20–35 nm wide observed by scanning electron microscopy. X-ray diffraction showed that TOCNFs are present in a cellulose crystal form I. The average crystal size corresponding to a fiber width was 4.2 nm, as determined from the diffraction pattern. Solid-state NMR shows that hemicellulose and lignin were mostly removed from SCGs via TEMPO-mediated oxidation, but small amounts of triacylglycerols remained in the TOCNFs. Thermogravimetric analysis of TOCNFs showed two major steps of thermal decomposition at 251 °C and 267 °C, which were higher than the coffee roasting temperature range. Furthermore, in order to investigate an interaction of these TOCNFs with a polymer, a SCG-derived TOCNF composite film with poly(vinyl alcohol) as a water-soluble polymer was prepared. We found the TOCNFs were successfully integrated into the polymer. The outcome of this study indicated that SCGs could be used as well as wood as an alternative source for producing TOCNFs, thus contributing to the development of sustainable green chemistry.

To perform molecular modeling or quantum chemistry calculations, a 3D file of a molecule of interest is required. The 3D file includes atomic types, coordinates, connectivity, and other structural data of a molecular model. A 3D file for a common molecule is available from existing data sources such as articles and databases in the web, or it can also be prepared using molecular modeling software. The use of computational chemistry techniques is expected to increase among researchers and students studying related subject matter if a molecular model built using a commercial molecular model kit can be directly subjected to computational analysis. Thus, we developed the Mm2cML software to facilitate the preparation of a 3D file from a real molecular model. Mm2cML is a web application based on structure from motion and multi-view stereo technologies in combination with a web interface. The effectiveness of the software was confirmed by evaluating the accuracy of vertical 3D models that were created using multiple 2D images. Further evaluation was performed through quantum chemistry calculations using 3D files obtained from vertical 3D models.

Several D-amino acid-containing peptides (DAACPs) with antimicrobial, cardio-excitatory, or neuronal activities have been found in several species. Here, we demonstrated the chiral separation of the antimicrobial peptide diastereomers, D-phenylseptin and L-phenylseptin using (S) and (R) 3,3'-phenyl-1,1'-binaphthyl-18-crown-6-ether columns (CR-I ( + ) and CR-I ( - ), respectively) and also investigated the underlying mechanism. First, using D-amino acid-containing tripeptide Phe-Phe-Phe-OH, we found that CR-I ( + ) could be used to recognize diastereomeric tripeptides containing an L-amino acid as the first residue. On the contrary, CR-I ( - ) enabled separation of a series of diastereomers with D-amino acid as the first residue. Therefore, we achieved separation of the stereoisomers using the chiral columns depending on the position of the D- amino acid in the peptide and demonstrated the orthogonality of separations of the chiral columns. Then, using CR-I (+), we separated amphibian antimicrobial peptide diastereomers, L- and D-phenylseptin, which have the sequences, L-Phe-L-Phe-LPhe and L-Phe-D-Phe-L-Phe at their N-termini, respectively. In order to understand the host-guest interactions, we performed molecular dynamics simulations for L-Phe-L-Phe-L-Phe tripeptide-CR-I molecule complex systems. Three hydrogen bonds between the N-terminal amine group -NH3+ and the crown ether oxygens were the dominant interactions. The hydrophobic interactions between phenyl-rings in the chiral selector unit of CR-I (+) and the side chains of 2nd and 3rd residues of the peptide also contributed to the affinity. Our results show that the CR-I ( + )-column can be applied for the separation of endogenous DAACPs generated by the post-translational modification.

The design and control of self-assembling biomaterials have significantly attracted attention over the last decades because of their broad ranges of applications. Here, we introduce the self-assembled fibers of the pyrene connected dipeptides, L-pyrenylalanine-L-phenylalanine (L-Pyr-L-Phe) and D-pyrenylalanine-L-phenylalanine (D-Pyr-L-Phe), and their structural analysis using experimental and computational techniques. While L-Pyr-L-Phe self-assembled into solid fibers, D-Pyr-L-Phe self-assembled into hydrogels with different morphologies. Fluorescence spectroscopy revealed monomer and red-shifted excimer emissions of the self-assembled L-Pyr-L-Phe and D-Pyr-L-Phe dipeptide nanostructures, respectively. This result was related to different C-13 and N-15 solid-state nuclear magnetic resonance (NMR) data on the backbone and side-chains of the self-assembled dipeptides. Molecular dynamics simulations demonstrated detailed information about the chirality effects of the dipeptides on their self-assembled structures.

Microwave heating is widely used to accelerate the organic synthesis reaction. However, the role of the nonthermal microwave effect in the chemical reaction has not yet been well characterized. The microwave heating processes of an ethanol-hexane mixed solution were investigated using in situ microwave irradiation nuclear magnetic resonance spectroscopy and molecular dynamics (MD) simulation. The temperature of the solution under microwave irradiation was estimated from the temperature dependence of the 1H chemical shifts (chemical shift calibrated (CSC)-temperature). The CSC-temperature increased to 58 °C for CH2 and CH3 protons, while it increased to 42 °C for OH protons during microwave irradiation. The CSC-temperature of CH2 and CH3 protons reflects the bulk temperature of solution by the thermal microwave effect. The lower CSC-temperature of the OH proton can be attributed to a nonthermal microwave effect. MD simulation revealed that electron dipole moments of OH groups ordered along the oscillated electric field decreased the entropy by absorbing microwave energy and simultaneously increased the entropy by dissipating energy to the solution as the thermal and nonthermal microwave effect. Ordered polar molecules interact to increase hydrogen bonds between OH groups as the nonthermal microwave effect, which explains the lower CSC-temperature of the OH protons. The nonthermal microwave effects contribute to the intrinsic acceleration of the organic reaction.

A grating-structured interface of a poly(3-hexylthiophene) (P3HT) and n-type [6,6]-phenyl-C61-butyric acid methyl ester (PCBM)-based bulk-heterojunction (BHJ) photovoltaic (PV) cell was designed and fabricated to obtain a desirable thickness distribution of the deposited bathocuproine (BCP) buffer layer to efficiently utilize its potentials. As a master mold of the grating-structure, a commercially available recordable digital versatile disc (DVD-R) substrate was employed. The grating-structured surface of the P3HT:PCBM layer was successfully produced by duplication from a poly(dimethylsiloxane) secondary mold using the spin cast molding technique. From morphological observations of the grating-structured surface covered with vapor-deposited BCP, we roughly estimated the ratio of the BCP thickness at “walls” to that at “top” and “bottom” regions to be ∼0.5. The grating-type BHJ PV cell with a 5-nm-thick BCP layer exhibited the maximum power-conversion efficiency (ηp) of 3.51%. Compared with the conventional flat-type BHJ PV cell with a 20-nm-thick BCP layer, the performance of the grating-type BHJ PV cell with a 20-nm-thick BCP layer was remarkably improved, owing to the contribution of the wall side contact, which provides a lower-barrier path of the electrons toward the cathode through the thinner BCP layer.

A β‐diketiminato‐based tridentate pincer‐type nickel(II) complex Ni‐NNP was prepared by the reaction of the nickel(II) precursor [NiCl 2 (2,4‐lutidine) 2 ] with the lithiated NNP ligand, which was generated in situ by the reaction of the NNP pro‐ligand H‐NNP with n BuLi. H‐NNP was prepared by the condensation of 4‐[(2,4,6‐trimethylphenyl)amino]pent‐3‐en‐2‐one with 2‐(diphenylphosphanyl)ethylamine. Ni‐NNP was characterized spectroscopically and by X‐ray diffraction, revealing a slightly distorted square‐planar geometry around the nickel center. Density functional theory calculations indicated that the highest occupied molecular orbital in Ni‐NNP is located at higher energy than those of three other homologous nickel(II) complexes, i.e., Ni‐ONN , Ni‐ONP , and Ni‐NNN , which contain β‐aminoketonato‐ or β‐diketiminato‐based pincer‐type ligands. The electronic and steric properties of Ni‐NNP effectively facilitated the cross‐coupling of aryl fluorides with aryl Grignard reagents.

In the case that the parameters to describe the force field, such as bond angles and charges, cannot be added to the library of a molecular dynamics (MD) simulation, self-development of the force field should be considered by performing quantum mechanics calculations and/or utilizing an automatic parameter generation tool. However, these techniques are not suitable for macromolecules with a large number of atoms. Typically, the force field of an oligomer containing three unit structures (a unit at both ends and a repeating unit at the center) is calculated and converted to polymer form (both ends + central part × n). Considering this, we recently developed the program o2p, which is a semi-automated program designed to set up the force field for polymers with repeating structures. However, it is difficult to apply this method to macromolecules with complex repeating structures. Thus, in this project, we developed PolyParGen, a new open-source automatic force field generation program for Gromacs that can relatively easily and reliably simulate the MD of complex macromolecules. The proposed program (1) divides the structure of the polymer into substructures with a number of atoms within the limit of the handling size for the automatic parameter generation tool program; then, (2) acquire the parameters for each divided substructure, and finally, (3) combine the parameters of these substructures to obtain the parameters for the whole polymer. By automating these processes, it is possible to acquire a parameter of a polymer having complicated structures. This program was evaluated by simulating the polymers P3EHT and F-P3EHT in chloroform. In agreement with previous reports, fluorination was found to cause F-P3EHT to adopt an extended structure, thereby indicating the effectiveness of the proposed program.

A -diketiminato-based tridentate pincer-type nickel(II) complex Ni-NNP was prepared by the reaction of the nickel(II) precursor [NiCl2(2,4-lutidine)2] with the lithiated NNP ligand, which was generated in situ by the reaction of the NNP pro-ligand H-NNP with nBuLi. H-NNP was prepared by the condensation of 4-[(2,4,6-trimethylphenyl)amino]pent-3-en-2-one with 2-(diphenylphosphanyl)ethylamine. Ni-NNP was characterized spectroscopically and by X-ray diffraction, revealing a slightly distorted square-planar geometry around the nickel

L-phenylseptin (L-Phes) and D-phenylseptin (D-Phes) are amphibian antimicrobial peptides isolated from the skin secretion of Hypsiboas punctatus. In the N-termini, L-Phes and D-Phes contain three consecutive phenylalanine residues, l-Phe-l-Phe-l-Phe and l-Phe-d-Phe-l-Phe, respectively. They are known to exhibit antimicrobial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Xanthomonas axonopodis pv. Glycines. However, their mechanism of action and the role of the D-amino acid residue have not been elucidated yet. In this study, the interactions of both peptides with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) were investigated by means of quartz crystal microbalance, circular dichroism, vibrational circular dichroism, 31P solid-state NMR, and molecular dynamics simulation. Both peptides have similar binding constants to the DMPC lipid bilayers, in the order of 106 M−1, and form an α-helix structure in the DMPC lipid bilayers. Both the peptides induce similar changes in the dynamics of DMPC lipids. Thus, in spite of the difference in the conformations caused by the chirality at the N-terminus, the peptides showed similar behavior in the membrane-bound state, experimentally and computationally.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Pharanois phoborhodopsin (ppR) from Natronomonas pharaonis is a transmembrane photoreceptor protein involved in negative phototaxis. Structural changes in ppR triggered by photoisomerization of the retinal chromophore are transmitted to its cognate transducer protein (pHtrll) through a cyclic photoreaction pathway involving several photointermediates. This pathway is called the photocycle. It is important to understand the detailed configurational changes of retinal during the photocycle. We previously observed one of the photointermediates (M-intermediates) by in situ photoirradiation solid-state NMR experiments. In this study, we further observed the C-13 cross-polarization magic-angle-spinning NMR signals of late photointermediates such as O- and N'-intermediates by illumination with green light (520 nm). Under blue-light (365 nm) irradiation of the M-intermediates, C-13 cross-polarization magic-angle-spinning NMR signals of 14- and 2013 C-labeled retinal in the O-intermediate appeared at 115.4 and 16.4 ppm and were assigned to the 13-trans, 15-syn configuration. The signals caused by the N'-intermediate appeared at 115.4 and 23.9 ppm and were assigned to the 13-cis configuration, and they were in an equilibrium state with the O-intermediate during thermal decay of the M-intermediates at -60 degrees C. Thus, photoirradiation NMR studies revealed the photoreaction pathways from the M- to O-intermediates and the equilibrium state between the N'- and O-intermediate. Further, we evaluated the detailed retinal configurations in the O- and N'-intermediates by performing a density functional theory chemical shift calculation. The results showed that the N'-intermediate has a 63 degrees twisted retinal state due to the 13-cis configuration. The retinal configurations of the O- and N'-intermediates were determined to be 13-trans, 15-syn, and 13-cis, respectively, based on the chemical shift values of [20-C-1(3)] and [14-C-1(3)] retinal obtained by photoirradiation solid-state NMR and density functional theory calculation.

Melittin is a bee venom peptide that disrupts acidic dimyristoylphosphatidylglycerol (DMPG) bilayers as well as neutral dimyristoylphosphatidylcholine (DMPC) bilayers. 13C chemical shift anisotropy of [1-13C]-labeled melittin showed oscillatory shifts with the index number of residues. Analysis of the 13C chemical shift oscillation properties indicated that melittin bound to a DMPG membrane adopts a bent α-helical structure with tilt angles for the N- and C-terminal helices of −32 and +30°, respectively. The transmembrane melittin in DMPG bilayers indicates that the peptide protrudes toward the C-terminal direction from the core region of the lipid bilayer to show a pseudotransmembrane bent α-helical structure [1, 2]. The structure topology and orientation of membrane-bound antibiotic alamethicin were studied using solid state NMR spectroscopy. 13C chemical shift interaction was observed for [1-13C]-labeled alamethicin. The chemical shift oscillation analysis was performed with the assumption that the adjacent peptide planes form an angle of 100° or 120° when it forms α-helix or 310-helix, respectively [2, 3]. These properties lead to an oscillation of the 13C chemical shift anisotropy with respect to the phase angle of the peptide plane. The chemical shift oscillation curves revealed that the N- and C-termini formed α-helix and 310-helix, and the N- and C-termini were tilted 17° and 32° to the bilayer normal, respectively. References [1] K. Norisada, N Javkhlantugs, D. Mishima, I. Kawamura, H. Saitô, K. Ueda, A. Naito, J. Phys. Chem.B. 2017, 121, 1802-1811. [2] A. Naito, N. Matsumori, A. Ramamoorthy, Biochim. Biophys. Acta, General Subject. In press 2017. DOI: 10.1016/j.bbagen.2017.06.004. [3] T. Nagao, D. Mishima, N. Javkhlantugs, J. Wang, D. Ishioka, K. Yokota, K. Norisada, I. Kawamura, K. Ueda, A. Naito, Biochim. Biophys. Acta, Biomembrane 2015, 1848, 2789-2798.

Solid-state nuclear magnetic resonance (NMR) spectroscopy provides significant structural information regarding the conformation and dynamics of a variety of solid samples. In this study, we recorded the 13C and 15N solid-state NMR spectra of a self-assembled isoleucine-phenylalanine (Ile–Phe–OH) dipeptide. Immediately after the addition of hexane to a solution of concentrated peptide in ethyl acetate, the peptide visually aggregated into a nanofiber. Then, we obtained well-resolved 13C and 15N NMR signals of the natural, isotopic-abundant Ile–Phe–OH peptide in the nanofiber. Furthermore, we calculated the chemical shift values of the reported crystal structure of the Ile–Phe dipeptide via the density functional theory (DFT) calculation and compared these results with the experimental values. Notably, the two sets of values were in good agreement with each other, which indicated that the self-assembled structure closely reflected the crystal structure. Therefore, herein, we demonstrated that solid-state NMR characterization combined with DFT calculations is a powerful method for the investigation of molecular structures in self-assembled short peptides.

Bombinin H4 is an antimicrobial peptide that was isolated from the toad Bombina variegata. Bombinin H family peptides are active against gram-positive, gram-negative bacteria, and fungi as well as the parasite Leishmania. Among them, bombinin H4 (H4), which contains d-allo-isoleucine (d-allo-Ile) as the second residue in its sequence, is the most active, and its l-isomer is bombinin H2 (H2). H4 has a significantly lower LC50 than H2 against Leishmania. However, the atomic-level mechanism of the membrane interaction and higher activity of H4 has not been clarified. In this work, we investigated the behavior of the conformations and interactions of H2 and H4 with the Leishmania membrane using 31P solid-state nuclear magnetic resonance (NMR), vibrational circular dichroism (VCD) spectroscopy, and molecular dynamics (MD) simulations. The generation of isotropic 31P NMR signals depending on the peptide concentration indicated the abilities of H2 and H4 to exert antimicrobial activity via membrane disruption. The VCD experiment and density functional theory calculation confirmed the different stability and conformations of the N-termini of H2 and H4. MD simulations revealed that the N-terminus of H4 is more stable than that of H2 in the membrane, in line with the VCD experiment data. VCD and MD analyses demonstrated that the first l-Ile and second d-allo-Ile of H4 tend to take a cis conformation. These residues function as an anchor and facilitate the easy winding of the helical conformation of H4 in the membrane. It may assist to quickly reach to the threshold concentration of H4 on the Leishmania membrane. This article is part of a Special Issue entitled: d-Amino acids: biology in the mirror, edited by Dr. Loredano Pollegioni, Dr. Jean-Pierre Mothet and Dr. Molla Gianluca.

Phosphonium ylide complexes of Mo and W formulated as [M(eta(3)-allyl){eta(2)-(NPh)(2)CH}(CO)(2)(CH2PR3)] (M = Mo, R = Me: 2a-Mo; M = Mo, R = Ph: 2b-Mo, and M = W, R = Me: 2a-W) were prepared by the reaction of amidinato(pyridine) complex, [M(eta(3)-allyl){eta(2)-(NPh)(2)CH}(CO)(2)(NC5H5)] (M = Mo: 1-Mo and M = W: 1-W), with a phosphonium ylide, CH2PR3 (R = Me, Ph), which was generated in situ by the reaction of the corresponding phosphonium salt with (BuLi)-Bu-n. These complexes were characterized spectroscopically, as well as by the X-ray diffraction. The phosphonium ylide ligand shows stronger electron donating ability toward the metal than N-heterocyclic carbene or phosphine ligands. This trend is supported by the comparison of the spectroscopic data and the DFT calculations. We also investigated the reactivity of the phosphonium ylide complexes 2-Mo with two-electron donors such as PEt3 and NHC. In the case of the PPh3 ylide complex (2b-Mo), the substitution reaction of the ylide ligand for the two-electron donors took place cleanly to yield the corresponding complexes. On the other hand, in the PMe3 ylide complex (2a-Mo), the substituted complexes formed but the unreacted ylide complex 2a-Mo was also present in the reaction mixture. These results show that the bond strength of the M-C(phosphonium ylide) bond is affected by the substituents on the phosphorus atom. (C) 2017 Elsevier B.V. All rights reserved.