Nuclear quantum effects on the intramolecular hydrogen bonds in biuret and biguanide.

We focus on the unique aspects of biuret and biguanide, which form six-membered ring structures via intramolecular hydrogen bonds. The proton donor and acceptor atoms differ between biuret and biguanide, leading to varying energy barrier heights for proton transfer. We performed path integral molecular dynamics (PIMD) simulations for biuret and biguanide to investigate the correlation between proton transfer and the degree of the delocalization of π-electrons in the six-membered ring framework structure. The results indicate that the π-electrons in the framework structure are delocalized regardless of the ease of intramolecular proton transfer.

Characteristics of membrane transport, metabolism, and target protein binding of cyclic depsipeptide destruxin E in HeLa cells.

Cyclic peptides have attracted attention as new modalities for drug development owing to their unique pharmacokinetic and pharmacodynamic properties. Destruxin E, a 19-membered cyclodepsipeptide, is a promising candidate drug for cancer therapy. The purpose of the present study was to clarify the molecular mechanisms underlying membrane transport, metabolism, and the binding for target molecules of destruxin E in human cervical carcinoma HeLa cells used as a model of cancer cells. The influx transport and the intracellular metabolism of destruxin E were non-saturable and saturable, respectively, at up to 10 µM. The intracellular amounts of destruxin E and destruxin E-diol after incubation of destruxin E with the cells significantly decreased at 4 °C compared to those at 37 °C. Destruxin E-diol, but not destruxin E, undergoes efflux transport out of cells via P-gp/MDR1/ABCB1 and BCRP/ABCG2. The epoxide hydrolase EPHX2 functions as a potent metabolizing enzyme that can convert the epoxide of destruxin E to the destruxin E-diol. Treatment with an EPHX2 inhibitor increased the intracellular destruxin E levels and enhanced the inhibitory activity of vacuolar type-H+ ATPase. These results suggest that epoxide hydrolase could be a regulatory factor for intracellular destruxin E levels and its pharmacological activity.

Ultrafine Spatial Modulation of Diazapyrene-Based Two-Dimensional Conjugated Covalent Organic Frameworks.

Tailormade bottom-up synthesis of covalent organic frameworks (COFs) from various functional building blocks offer not only tunable topology and pore size but also multidimensional properties. High crystallinity is one of the prerequisites for their structures and associated physicochemical properties. Among different π-conjugated motifs for constructing COFs, pyrene-based tetragonal structures are effective in achieving highly ordered and crystalline states. In the present research, we demonstrated that the substitution of pyrene with 2,7-diazapyrene produces nearly "flat" structures of two-dimensional (2D) COF layers by controlling the torsional angle of linker molecules. Featuring finite pore diameters and excellent thermodynamic stability of ∼500 °C, ordered face-to-face (slipped AA) stacking arrangements were produced. Extended electrical conjugation spanning 2D frames with modest optical bandgaps (Eg) of ∼2.1 eV shows the planar character of diazapyrene-based COFs. The stacking of the conjugated 2D frames with small Eg values is also beneficial for the formation of highly stable conducting pathways in the crystalline state, which was confirmed by the results of the microwave conductivity measurements. Nitrogen centers in diazapyrene units also play a key role as the active sites for proton transfer, and the maximum proton conductivity of σ = 10-2 S cm-1 was achieved along the cocontinuous nanopore structures surrounded by the active sites. Results show that tetragonal COFs based on diazapyrene can be used as a highly crystalline two-dimensional material with special electrical and proton-conducting capabilities.

Nuclear quantum and H/D isotope effects on aromaticity: path integral molecular dynamics study.

Aromaticity is an important concept in organic chemistry, and thus, many theoretical and experimental studies have been conducted so far. However, the majority of theoretical studies have concentrated on the aromaticity of the stationary point structures. Herein, the influence of nuclear quantum fluctuation (nuclear quantum effects: NQEs) and thermal fluctuation on the aromaticity of benzene have been analyzed by path integral molecular dynamics (PIMD) simulation. The PIMD simulations revealed that the NQEs affected not only the C-H bonds but also the C-C bonds. The HOMA and NICS calculations demonstrated that the aromaticity decreased due to the NQEs of carbon atoms, attributed to an increase in the contribution from specific vibrational modes strongly correlated with benzene's aromaticity.

Theoretical study of short-range exchange interaction based on semiconductor dielectric function model toward time-dependent dielectric density functional theory.

This study explores various models of semiconductor dielectric functions, with a specific emphasis on the large wavenumber spectrum and the derivation of the screened exchange interaction. Particularly, we discuss the short-range effect of the screened exchange potential. Our investigation reveals that the short-range effect originating from the high wavenumber spectrum is contingent upon the dielectric constant of the targeted system. To incorporate dielectric-dependent behaviors concerning the short-range aspect into the dielectric density functional theory (DFT) framework, we utilize the local Slater term and the Yukawa-type term, adjusting the ratio between these terms based on the dielectric constant. Additionally, we demonstrate the efficacy of the time-dependent dielectric DFT method in accurately characterizing the electronic structure of excited states in dyes and functional molecules. Several theoretical approaches have incorporated parameters dependent on the system to elucidate short-range exchange interactions. Our theoretical analysis and discussions will be useful for those studies.

Nuclear quantum effects in phase transition between Ice VII and Ice X.

The theoretical modeling of high-pressure ice remains challenging owing to the complexity in accurately reflecting its properties attributable to nuclear quantum effects. To explore the nuclear quantum effects of the phase transition between Ice VII and Ice X, we introduce an approach based on ab initio path-integral molecular dynamics. The results indicate that quantum effects facilitate the phase transition, with the observed isotope effects consistent with the experimental outcomes. We demonstrate that quantum effects manifest differently across ice phases: In Ice VII, quantum effects reduce the pressure through the centralization of protons. In contrast, in Ice X, quantum effects increase the pressure owing to the increased kinetic energy of zero-point vibration.

Hypoxia suppresses glucose-induced increases in collective cell migration in vascular endothelial cell monolayers.

Blood glucose levels fluctuate during daily life, and the oxygen concentration is low compared to the atmosphere. Vascular endothelial cells (ECs) maintain vascular homeostasis by sensing changes in glucose and oxygen concentrations, resulting in collective migration. However, the behaviors of ECs in response to high-glucose and hypoxic environments and the underlying mechanisms remain unclear. In this study, we investigated the collective migration of ECs simultaneously stimulated by changes in glucose and oxygen concentrations. Cell migration in EC monolayer formed inside the media channels of microfluidic devices was observed while varying the glucose and oxygen concentrations. The cell migration increased with increasing glucose concentration under normoxic condition but decreased under hypoxic condition, even in the presence of high glucose levels. In addition, inhibition of mitochondrial function reduced the cell migration regardless of glucose and oxygen concentrations. Thus, oxygen had a greater impact on cell migration than glucose, and aerobic energy production in mitochondria plays an important mechanistic role. These results provide new insights regarding vascular homeostasis relative to glucose and oxygen concentration changes.

Location of the Shared Proton in Proton-Bound Dimer Compound of Hydrogen Sulfate and Formate: Path Integral Molecular Dynamics Study.

The structure of the proton-bound dimer compound of hydrogen sulfate and formate has been studied by considering nuclear quantum effects (NQEs) using the path integral molecular dynamics method. This study unveiled the location of the shared proton and answered the following question: "Is the shared proton localized on either an anion or located around the center of two anions?" We have elucidated that the shared proton is distributed in the region beyond the transition state due to the NQEs, even though the shared proton did not completely overcome the transition state for the proton shuttle.

Molecular Mechanism of SLC6A8 Dysfunction with c.1699T > C (p.S567P) Mutation in Cerebral Creatine Deficiency Syndromes.

Cerebral creatine deficiency syndromes (CCDS) are neurodevelopmental disorders caused by a decrease in creatine levels in the central nervous system (CNS) due to functional mutations in creatine synthetic enzymes or creatine transporter (CRT/SLC6A8). Although SLC6A8 mutations have been reported to be the most frequent cause of CCDS, sufficient treatment for patients with CCDS harboring SLC6A8 mutations has not yet been achieved. This study aimed to elucidate the molecular mechanism of SLC6A8 dysfunction caused by the c. 1699T > C missense mutation, which is thought to induce dysfunction through an unidentified mechanism. A study on SLC6A8-expressing oocytes showed that the c.1699T > C mutation decreased creatine uptake compared to that in wild-type (WT) oocytes. In addition, a kinetics study of creatine uptake revealed that the c.1699T > C mutation reduced the maximum uptake rate but not Michaelis-Menten constant. In contrast, the c.1699T > C mutation did not attenuate SLC6A8 protein levels or alter its cellular localization. Based on the SLC6A8 structure in the AlphaFold protein structure database, it is possible that the c.1699T > C mutation alters the interaction between the S567 and Y143 residues of SLC6A8, leading to decreased creatine transport function. These findings contribute to the understanding of the pathology of CCDS and to the development of strategies for CCDS treatment.

A path integral molecular dynamics study on the muoniated xanthene-thione molecule.

A positive Mu is a useful tool for investigating the spin density of radical species. The theoretical estimation of its behavior in a molecule requires the inclusion of a quantum effect due to the small mass of muonium. Herein, we performed ab initio a path integral molecular dynamics (PIMD) simulation, which accurately included a multi-dimensional quantum effect, for muoniated 9H-xanthene-9-thione (µXT). Our results showed that the quantum effect significantly increased the hyperfine coupling constant (HFCC) value of µXT, which qualitatively improved the calculated HFCC value, compared to the experimental one. In the PIMD simulation, the bond length between muonium and sulfur in µXT is longer than that between hydrogen and sulfur in a hydrogenated 9H-xanthene-9-thione (HXT), leading to a spin density transfer from XT (9H-xanthene-9-thione) to muonium due to neutral dissociations. Additionally, we found that the S-Mu bond in µXT prefers a structure perpendicular to the molecular plane, where the interaction between Mu and the singly occupied molecular orbital of µXT is the strongest. These structural changes resulted in a larger HFCC value in the PIMD simulation of µXT.

Theoretical Study of the Molecular Passivation Effect of Lewis Base/Acid on Lead-Free Tin Perovskite Surface Defects.

Extensive research has been recently conducted to improve the power conversion efficiency (PCE) of perovskite solar cells. However, the charge carriers are easily trapped by the defect sites located at the interface between the perovskite layer and the electrode, which decreases the PCE. To reduce such defect sites, the passivation technique is frequently employed to coat small molecules on the perovskite surface during the manufacturing process. To clarify the passivation mechanism from a molecular viewpoint, we performed density functional theory calculations to target Pb-free Sn perovskites (CH3NH3SnI3). We investigated the passivation effect of Lewis base/acid molecules, such as ethylene diamine (EDA) and iodopentafluorobenzene (IPFB), and discussed behaviors of the defect levels within the bandgap as they have strong negative impacts on the PCE. The adsorption of EDA/IPFB on the Sn perovskite surface can remove the defect levels from the bandgap. Furthermore, we discuss the importance of interactions with molecular orbitals.

Stability and bonding nature of positronic lithium molecular dianion.

We studied the stability of a system consisting of a positron (e+) and two lithium anions, [Li-; e+; Li-], using first-principles quantum Monte Carlo calculations combined with the multi-component molecular orbital method. While diatomic lithium molecular dianions Li22- are unstable, we found that its positronic complex can form a bound state with respect to the lowest energy decay into the dissociation channel Li2- and a positronium (Ps). The [Li-; e+; Li-] system has the minimum energy at the internuclear distance of ∼3 Å, which is close to the equilibrium internuclear distance of Li2-. At the minimum energy structure both an excess electron and a positron are delocalized as orbiting around the Li2- molecular anion core. A dominant feature of such a positron bonding structure is described as the Ps fraction bound to Li2-, unlike the covalent positron bonding scheme for the electronically isovalent [H-; e+; H-] complex.

Nuclear quantum and H/D isotope effects on intramolecular hydrogen bond in curcumin.

Curcumin and its derivatives possess intramolecular low-barrier hydrogen bonds for intramolecular proton transfer. The π-delocalization in the OCCCO framework of the hydrogen bond in these compounds is reorganized concomitantly with the proton transfer. To characterize the hydrogen bond and π-delocalization, we performed path integral molecular dynamics simulations, revealing that although the proton migration and reorganization of the π-delocalized structure showed a positive correlation, the correlation was weak.

Improved activity for the oxygen evolution reaction using a tiara-like thiolate-protected nickel nanocluster.

Practical electrochemical water splitting and carbon-dioxide reduction are desirable for a sustainable energy society. In particular, facilitating the oxygen evolution reaction (OER, the reaction at the anode) will increase the efficiency of these reactions. Nickel (Ni) compounds are excellent OER catalysts under basic conditions, and atomically precise Ni clusters have been actively studied to understand their complex reaction mechanisms. In this study, we evaluated the geometric/electronic structure of tiara-like metal nanoclusters [Nin(PET)2n; n = 4, 5, 6, where PET refers to phenylethanethiolate] with the same SR ligand. The geometric structure of Ni5(SR)10 was determined for the first time using single-crystal X-ray diffraction. Additionally, combined electrochemical measurements and X-ray absorption fine structure measurements revealed that Ni5(SR)10 easily forms an OER intermediate and therefore exhibits a high specific activity.

Direct Elucidation of the Vibrationally Averaged Structure of Benzene: A Path Integral Molecular Dynamics Study.

Path integral molecular dynamics (PIMD) simulations for C6H6, C6D6, and C6T6 have been carried out to directly estimate the distribution of projected C-H(D,T) bond lengths onto the principal axis plane. The average values of raw C-H(D,T) bond lengths obtained from PIMD simulations are in the order of ⟨RC-H⟩ > ⟨RC-D⟩ > ⟨RC-T⟩ due to the anharmonicity of the potential energy curve. However, the projected C-H(D,T) bond lengths are almost the same as those reported by Hirano et al. [J. Mol. Struct. 2021, 1243, 130537]. Our PIMD simulations directly and strongly support the explanation by Hirano et al. for the experimental observations that almost the same projected C-H(D) bond lengths are found for C6H6 and C6D6. The PIMD simulations also predicted the same projected bond lengths for C6T6 as those of C6H(D)6. In addition to the previous local mode analysis, the present PIMD simulations predicted, for benzene isotopologues, that the vibrationally averaged structure is planar but non-flat.

Molecular Dynamics Study on the Structure-Property Relationship of Self-Assembled Gear-Shaped Amphiphile Molecules with/without Methyl Groups.

Gaining insight into the encapsulation mechanism is important for controlling the encapsulation rate toward the self-assembly of gear-shaped amphiphile molecules (GSAs). To this aim, we conducted molecular dynamics (MD) simulations for three different hexameric nanocubes (1612+, 2612+, and 3612+) of GSAs (12+, 22+, and 32+, respectively) to elucidate the quantitative structure-property relationship between the stability of the nanocubes and the rate of encapsulation of a guest molecule. The 12+, 22+, and 32+ monomers differ from each other in the number of methyl groups, having three, zero, and two methyl groups, respectively. The 3612+ hexamer has methyl groups only on the equatorial region. In the cases of the simulations of 1612+ and 3612+, the cubic structures are maintained due to a tight triple-π stacking around the equator region. Meanwhile, 2612+ deforms easily due to the occurrence of a large fluctuation. These results indicate that the methyl groups on the equator are crucial to stabilize the nanocubes. The encapsulation of an iodide ion as a guest molecule is revealed to occur through the pole region via a gap that is easily formed in the nanocubes without methyl groups on the poles. Our study clearly suggests that self-assembled nanocubes can be designed to attain a specific stability and encapsulation efficiency simultaneously.

Quantitative Targeted Absolute Proteomics for Better Characterization of an In Vitro Human Blood-Brain Barrier Model Derived from Hematopoietic Stem Cells.

We previously developed an in vitro model of the human blood-brain barrier (BBB) based on the use of endothelial cells derived from CD34+-hematopoietic stem cells and cultured with brain pericytes. The purpose of the present study was to provide information on the protein expression levels of the transporters, receptors, tight junction/adherence junction molecules, and transporter-associated molecules of human brain-like endothelial cells (hBLECs). The absolute protein expression levels were determined by liquid chromatography-mass spectrometry-based quantitative targeted absolute proteomics and compared with those from human brain microvessels (hBMVs). The protein levels of CD144, CD147, MRP4, Annexin A6 and caveolin-1 showed more than 3-fold abundance in hBLECs, those of MCT1, Connexin 43, TfR1, and claudin-5 showed less than 3-fold differences, and the protein levels of other drug efflux transporters and nutrient transporters were less represented in hBLECs than in hBMVs. It is noteworthy that BCRP was more expressed than MDR1 in hBLECs, as this was the case for hBMVs. These results suggest that transports mediated by MCT1, TfR1, and claudin-5-related tight junction function reflect the in vivo BBB situation. The present study provided a better characterization of hBLECs and clarified the equivalence of the transport characteristics between in vitro BBB models and in vivo BBB models using LC-MS/MS-based protein quantification.

Decomposition analysis on the excitation behaviors of thiazolothiazole (TTz)-based dyes via the time-dependent dielectric density functional theory approach.

Thiazolothiazole (TTz)-based materials have been attracting much attention because of their widespread applications. In this paper, we discuss the excited electronic behaviors of asymmetric TTz dyes in solvents based on the time-dependent dielectric density functional theory method. Based on dipole moment and charge distribution (population) analyses, we discuss large intramolecular electron transfers, which are triggered by photon excitations, toward the acceptor part of dyes. In addition, we explore the contributions of geometrical changes and solvent reorientations (reorganizations) to the solvatofluorochromic phenomena based on a decomposition technique. The decomposition analysis shows that the solvent reorientation effect mainly contributes to changes in the fluorescent spectra in response to solvents.

Theoretical investigations of positron affinities and their structure-dependent properties of carbon dioxide clusters (CO2)n (n = 1-5).

Although positron binding to van der Waals intermolecularly bonded clusters of non-polar carbon dioxide (CO2) molecules was experimentally suggested, the positron binding feature has been poorly understood. We investigated positron affinities (PAs) by means of multi-component configuration interaction calculations for various structures of (CO2)n (n = 1-5) obtained by the single-component artificial force induced reaction (SC-AFIR) method. Our calculations showed that CO2 monomers do not bind a positron, whereas positron affinities for clusters tend to increase with an increase in the cluster size. Our regression analyses for determining PAs with electrostatic and structural properties of conformations revealed a significant conformer effect due to which structural characteristics such as flatness may have a strong influence on PA for loosely bound positronic complexes of (CO2)n.

A comprehensive theoretical study of positron binding and annihilation properties of hydrogen bonded binary molecular clusters.

We studied the positron binding and annihilation of hydrogen bonded binary molecular clusters containing small inorganic molecules such as water, hydrogen fluoride, ammonia, hydrogen sulfide, hydrogen chloride, and phosphine, using first-principles calculation. While unimolecular systems of these species mostly exhibit no or very small positron binding energies (positron affinities), we found that all of their hydrogen bonding clusters have greater positive positron affinities. The permanent dipole moment enhanced by the formation of the intermolecular hydrogen bond acts as a dominant parameter to bind a positron for a given proton donor, whereas it is insufficient for reproducing the dependence of the positron affinity on substitutions of the proton donor. By multiple regression analyses with inherent properties of the clusters, we found a reasonable model with additional effective parameters represented by, particularly, the number of hydrogen atoms free from the hydrogen bond. By density analyses for the single-particle and electron-positron collision probabilities, we revealed that these effective parameters are associated with the electronic structure changes induced by the hydrogen bond and positron binding, which have important roles to enhance the electron-positron contact densities due to the proton-screening effect.