Ab Initio Molecular Orbital Calculations Research Articles

In Silico Design of Natural Inhibitors of ApoE4 from the Plant Moringa oleifera: Molecular Docking and Ab Initio Fragment Molecular Orbital Calculations.

Alzheimer's disease (AD) is a neurological disease, and its signs and symptoms appear slowly over time. Although current Alzheimer's disease treatments can alleviate symptoms, they cannot prevent the disease from progressing. To accurately diagnose and treat Alzheimer's disease, it is therefore necessary to establish effective methods for diagnosis. Apolipoprotein E4 (ApoE4), the most frequent genetic risk factor for AD, is expressed in more than half of patients with AD, making it an attractive target for AD therapy. We used molecular docking simulations, classical molecular mechanics optimizations, and ab initio fragment molecular orbital (FMO) calculations to investigate the specific interactions between ApoE4 and the naturally occurring compounds found in the plant Moringa Oleifera. According to the FMO calculations, quercetin had the highest binding affinity to ApoE4 among the sixteen compounds because its hydroxyl groups generated strong hydrogen bonds with the ApoE4 residues Trp11, Asp12, Arg15, and Asp130. As a result, we proposed various quercetin derivatives by introducing a hydroxyl group into quercetin and studied their ApoE4 binding properties. The FMO data clearly showed that adding a hydroxyl group to quercetin improved its binding capacity to ApoE4. Furthermore, ApoE4 Trp11, Asp12, Arg15, and Asp130 residues were discovered to be required for significant interactions between ApoE4 and quercetin derivatives. They had a higher ApoE4 binding affinity than our previously proposed epicatechin derivatives. Accordingly, the current results evaluated using the ab initio FMO method will be useful for designing potent ApoE4 inhibitors that can be used as a candidate agent for AD treatment.

Mechanisms of the photodarkening in chalcogenide glasses: Strains or defects?

The photodarkening is observed in many chalcogenide glasses, while its mechanism remains controversial. There are few reports which discuss the whole process. We consider the mechanism through ab initio molecular-orbital calculations for the simplest systems, elemental S and Se clusters. The results manifest that valence-alternation pair (VAP) defects are unstable in the dark, thus it cannot be an origin. On the other hand, intimate VAPs can be quasi-stable, while those affect only band-edge states, which is contradictory with observed spectral modifications. By contrast, strains in van-der-Waals (VDW) distances are likely to broaden the lone-pair electron band. A refined bond-twisting model is able to trace such a process, including annealing stage. Quantitatively, the maximal red-shift of ∼0.1 eV can be related with quasi-stable strains containable in a medium-range volume of ∼1 nm3, which can be thermally released through atomic twisting motions over angular barriers with a height of ∼1 eV.

Computational Approach for Molecular Design of Small Organic Molecules with High Hole Mobilities in Amorphous Phase Using Random Forest Technique and Computer Simulation Method

Abstract A molecular design system of small organic molecules was developed to realize high hole mobility in the amorphous phase by using the random forest (RF) technique and a computer simulation method. Since there was no accessible datasets of the hole mobilities in the amorphous phase, we have constructed a datasets of experimental hole mobilities for 321 organic molecules with calculated MO energies to utilize machine learning techniques for molecular design procedures. RF was applied to the machine learning technique using the constructed datasets. The optimized RF exhibited correlation coefficients of 0.885 and 0.764 for the training and testing datasets, respectively. The modified ChemTS to use optimized RF was adapted to design molecules with high hole mobilities. The successive conduction (SC) model that uses ab initio molecular orbital (MO) calculations and the Marcus theory was adapted to ensure the predicted mobilities. The generated molecules were verified to have high calculated hole mobility (the order of 10−2 cm2/Vs) owing to the highest transfer integral and lowest reorganization energy by the theoretical successive conduction (SC) model. The datasets and programs used in this work were publicly released on GitHub.

Performance and Mechanism of Chlorine Dioxide on BTEX Removal in Liquid and Indoor Air.

With the development of the chemical industry, benzene, toluene, ethylbenzene, and xylene (BTEX) have gradually become the major indoor air pollutants. Various gas treatment techniques are widely used to prevent the physical and mental health hazards of BTEX in semi-enclosed spaces. Chlorine dioxide (ClO2) is an alternative to chlorine as a secondary disinfectant with a strong oxidation ability, a wide range of action, and no carcinogenic effects. In addition, ClO2 has a unique permeability which allows it to eliminate volatile contaminants from the source. However, little attention has been paid to the removal of BTEX by ClO2, due to the difficulty of removing BTEX in semi-enclosed areas and the lack of testing methods for the reaction intermediates. Therefore, this study explored the performance of ClO2 advanced oxidation technology on both liquid and gaseous benzene, toluene, o-xylene, and m-xylene. The results showed that ClO2 was efficient in the removal of BTEX. The byproducts were detected by gas chromatography-mass spectrometry (GC-MS) and the reaction mechanism was speculated using the ab initio molecular orbital calculations method. The results demonstrated that ClO2 could remove the BTEX from the water and the air without causing secondary pollution.

Proposal of novel ApoE4 inhibitors from the natural spice Cinnamon for the treatment of Alzheimer's disease: Ab initio molecular simulations

Alzheimer's disease (AD), one of the most common neurodegenerative diseases, is a major factor contributing to cognitive impairment in older adults. Current therapeutic treatments can only relieve the symptoms of AD, but they cannot stop the progression of the disease because it takes a long time for clinical symptoms to manifest. Therefore, it is essential to develop effective diagnostic strategies for early detection and treatment of AD. As the most common genetic risk factor for AD, apolipoprotein E4 (ApoE4) is present in more than half of patients with AD, and it can be a target protein for AD therapy. We used molecular docking, classical molecular mechanics optimizations, and ab initio fragment molecular orbital (FMO) calculations to investigate the specific interactions between ApoE4 and Cinnamon-derived compounds. Of the 10 compounds, epicatechin was found to have the highest binding affinity to ApoE4 because the hydroxyl groups of epicatechin form strong hydrogen bonds with the Asp130 and Asp12 residues of ApoE4. Therefore, we proposed some epicatechin derivatives by adding a hydroxyl group to epicatechin and studied their interactions with ApoE4. The FMO results indicate that the addition of a hydroxyl group to epicatechin increases its binding affinity to ApoE4. It is also revealed that the Asp130 and Asp12 residues of ApoE4 are important for the binding between ApoE4 and the epicatechin derivatives. These findings will help propose potent inhibitors against ApoE4, leading to a proposal for effective therapeutic candidates for AD.

Structure and Diffusive Properties of Water in Polymer Hydrogels.

To investigate the diffusive properties of water in hydrogels, ab initio molecular orbital and molecular dynamics calculations of poly-N,N-dimethylacrylamide-water systems were performed. The results show that the mean diffusion coefficient of water drastically decreases in the middle dehydration stage. In this stage, the mobilities of water are restrained because part of the water forms hydrogen bonds to bind polymer chains due to a glass transition. In addition to the three well-known types of water (i.e., bound, intermediate, and free water) around hydrophilic polymers in hydrogels, our results suggest that the intermediate water can be further classified into two types: first and second intermediate water. The bound and first intermediate water acts as a cross-linker between polymer chains, even if the polymer does not form intra- or intermolecular bonds itself. The diffusive properties of water might have important implications for the interpretation of properties of polymer hydrogels.

Natural inhibitors for severe acute respiratory syndrome coronavirus 2 main protease from Moringa oleifera, Aloe vera, and Nyctanthes arbor-tristis: molecular docking and ab initio fragment molecular orbital calculations.

The novel coronavirus 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide, and new drug treatments for COVID-19 are urgently required. To find the potential inhibitors against the main protease (Mpro) of SARS-CoV-2, we investigated the inhibitory potential of naturally occurring compounds from the plants Moringa oleifera, Aloe vera, and Nyctanthes arbor-tristis, using molecular docking, classical molecular mechanics optimizations, and ab initio fragment molecular orbital (FMO) calculations. Of the 35 compounds that we simulated, feralolide from Aloe vera exhibited the highest binding affinity against Mpro. Therefore, we proposed novel compounds based on the feralolide and investigated their binding properties to Mpro. The FMO results indicated that the introduction of a hydroxyl group into feralolide significantly enhances its binding affinity to Mpro. These results provide useful information for developing potent Mpro inhibitors.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11224-022-02021-y.

Compact formulae for three-center nuclear attraction integrals over exponential type functions

In any ab initio molecular orbital calculations, the major task involves the computation of the so-called molecular multi-center integrals. Multi-center integral calculations is a very challenging mathematical problem in nature. Quantum mechanics only determines which integrals we evaluate, but the techniques employed for their evaluations are entirely mathematical. The three-center nuclear attraction integrals occur in a very large number even for small molecules and are among of the most difficult molecular integrals to compute efficiently. In the present contribution, we report analytical expressions for the three-center nuclear attraction integrals over exponential type functions. We describe how to compute the formula to obtain an efficient evaluation in double precision arithmetic. This requires the rational minimax approximants that minimize the maximum error on the interval of evaluation.

Machine Learning Predictor Models in the Electronic Properties of Alkanes based on Degree-Topology Indices

New topology indices that are degree-based have been introduced to represent molecular structure from chemical graph theory. The indices give a new sight into the physical properties of the chemical compounds. The correlation of physiochemical properties with chemical graph theory can be done using the Quantitative Structure Properties Relationship (QSPR). Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) are two basic electronic properties that describe the physiochemical of molecular structure. In computational chemistry, HOMO and LUMO can be calculated by ab initio molecular orbital calculation such as semi-empirical and density functional theory (DFT) method. However, these methods are time-consuming computations. In this paper, predictor model of HOMO and LUMO were developed using Machine Learning algorithms namely Linear Regression, Ridge Regression, LASSO Regression and Elastic Net Regression. The results showed that the performance achievement of each of the machine learning algorithms varied in accordance to the topology indices descriptors and the most outperformed model was presented by Linear Regression with the Moment Balaban Indices (JJ). This paper provides the fundamental design and implementation framework of predicting the HOMO and LUMO electronic properties

Proposal of selective inhibitor for bacterial zinc metalloprotease: Molecular mechanics and ab initio molecular orbital calculations

The zinc metalloprotease pseudolysin (PLN) secreted from Pseudomonas aeruginosa degrades extracellular proteins to produce bacterial nutrition, and various types of PLN inhibitors have been developed to suppress the bacterial growth. However, as the structure of the ligand-binding pocket of PLN has large similarities to those of human matrix metalloproteinases (MMPs) and other human zinc metalloprotease, there is a risk that PLN inhibitors also inhibit human zinc proteases. In this study, we propose a novel agent that may bind stronger to PLN than to MMPs. The compound is proposed based on the specific molecular interactions between existing agents and PLN/MMP metalloproteases evaluated by the present molecular simulations. First, we confirmed that the binding energies of PLN agents evaluated using the ab initio fragment molecular orbital method were comparable to the IC50 values obtained through previous experiments. In addition, the specific molecular interactions between these agents and MMP-9 were investigated to elucidate the fact that some of the agents bind weaker to MMP than PLN. Based on the results, we proposed a novel agent having a succinimide group introduce by a hydroxamic acid group and investigated its binding properties with PLN and MMP. The results may provide useful information for the development of potent inhibitors for PLN with few potential side effects in human bodies.

Basic Study on Organic Electron Transfer Reactions by Electrochemistry Combined with Quantum Chemical Calculations

This review summarizes the results of the author's basic research on organic electrochemistry conducted at Gifu Pharmaceutical University over about 40 years. After completing graduate school, the author became a research associate in Prof. Tanekazu Kubota's laboratory and started research on molecular spectroscopy in 1983. After Prof. Kubota retired in 1989, the author continued investigations in the field of organic electrochemistry as an independent researcher. At that time, a research environment in which ab initio molecular orbital calculations can be used as an analytical tool for experimental research was developed, and the author commenced research on organic electrochemistry combined with quantum chemical calculations as a lifework. The author's research topics were basic research on the molecular theory of redox potentials of organic molecules, molecular design of functional molecules, intermolecular interactions of organic molecules involving electron transfers and electron transfer systems composed of bioactive quinones, and analytical application research based on the basic electrochemistry. In this review article, the essence of the research results is introduced while reflecting on the existing situation at the time of the research. The author concludes the review by expressing gratitude to all colleagues for supporting the research in the author's laboratory.

Dynamic Cooperativity of Ligand-Residue Interactions Evaluated with the Fragment Molecular Orbital Method.

By the splendid advance in computation power realized with the Fugaku supercomputer, it has become possible to perform ab initio fragment molecular orbital (FMO) calculations for thousands of dynamic structures of protein-ligand complexes in a parallel way. We thus carried out electron-correlated FMO calculations for a complex of the 3C-like (3CL) main protease (Mpro) of the new coronavirus (SARS-CoV-2) and its inhibitor N3 incorporating the structural fluctuations sampled by classical molecular dynamics (MD) simulation in hydrated conditions. Along with a statistical evaluation of the interfragment interaction energies (IFIEs) between the N3 ligand and the surrounding amino-acid residues for 1000 dynamic structure samples, in this study we applied a novel approach based on principal component analysis (PCA) and singular value decomposition (SVD) to the analysis of IFIE data in order to extract the dynamically cooperative interactions between the ligand and the residues. We found that the relative importance of each residue is modified via the structural fluctuations and that the ligand is bound in the pharmacophore in a dynamic manner through collective interactions formed by multiple residues, thus providing new insight into structure-based drug discovery.

Effects of Polysilane Addition to Chlorobenzene and High Temperature Annealing on CH3NH3PbI3 Perovskite Photovoltaic Devices

CH3NH3PbI3 perovskite photovoltaic devices treated with a polysilane layer were fabricated and characterized. Decaphenylcyclopentasilane (DPPS) in chlorobenzene solution was deposited at the surface of the perovskite layer, and the resulting device was annealed at 140–260 °C. The photoconversion efficiencies of the DPPS-treated device remained high even after 255 days in ambient air. Raman scattering spectroscopy and ab initio molecular orbital calculations of DPPS suggested that it increased hole transport efficiency in the treated devices, which was confirmed from the high shunt resistances of the DPPS-treated devices.

Proposal of novel natural inhibitors of severe acute respiratory syndrome coronavirus 2 main protease: Molecular docking and ab initio fragment molecular orbital calculations

This paper proposes natural drug candidate compounds for the treatment of coronavirus disease 2019 (COVID-19). We investigated the binding properties between the compounds in the Moringa oleifera plant and the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 using molecular docking and ab initio fragment molecular orbital calculations. Among the 12 compounds, niaziminin was found to bind the strongest to Mpro. We furthermore proposed novel compounds based on niaziminin and investigated their binding properties to Mpro. The results reveal that the introduction of a hydroxyl group into niaziminin enhances its binding affinity to Mpro. These niaziminin derivatives can be promising candidate drugs for the treatment of COVID-19.

Synthesis, characterization and modeling of stable radical functionalized monothiophenes

The synthesis, characterization and modeling of two oligothiophenes bearing stable radicals are reported. The radical precursors 2,4-dimethyl-6-(6-(thiophen-2-yl)pyridin-2-yl)-1,2,4,5-tetrazinan-3-one (3) and 2,4-dimethyl-6-(6-(thiophen-3-yl)pyridin-2-yl)-1,2,4,5-tetrazinan-3-one (4) were prepared in a good yield (80–90%) by condensation of the appropriate thiophene-pyridine carboxaldehyde and 2,4-dimethylcarbonohydrazide. The oxidation of 3 and 4 using 1,4-benzoquinone in methanol yields radicals 5 and 6 (6-(3-thienyl)-pyridine-2-(1,5-dimethyl-6-oxoverdazyl)), respectively. All these new compounds are stable in air and organic solvents. Radicals 5 and 6 were characterized by EPR and Infrared as evidence by the shift of the carbonyl stretching of the precursors from 1629 cm−1–1660 cm−1 for the corresponding radicals. Ab initio molecular orbital calculations and spin densities were used to ascertain electronic properties of 3–6.

Proposal of novel potent inhibitors against androgen receptor based on ab initio molecular orbital calculations

The androgen receptor (AR), a family of nuclear receptor proteins, stimulates the transcription of androgen-responsive genes. As its abnormal activation can cause the progression of prostate cancer, numerous types of ligands for AR have been developed as promising antagonists for the treatment of prostate cancer. We previously investigated the specific interactions between AR and nine types of existing non-steroidal ligands, using molecular simulations based on molecular mechanics and ab initio fragment molecular orbital methods. The results were confirmed to be comparable to the binding affinities of these ligands observed in experiments. We here propose novel ligands as potent inhibitors against AR and investigate their binding properties to AR, using the same molecular simulations. The results indicate that the most promising ligand binds stronger to AR than the existing non-steroidal ligands, and that our proposed ligand binds strongly to a mutant-type AR, which has drug resistance to the existing non-steroidal ligands.

Hydration of the Zwitterionic and Protonated Forms of Glycine Betaine Probed by Soft X-ray Emission Spectroscopy Coupled with Chemometrics.

Soft X-ray absorption and emission spectra of glycine betaine (GB) have been measured at the O K-edge in neutral and strongly acidic solutions. The absorption spectra of the neutral solutions have a resonance peak at 532.6 eV, assigned to the transition to the π* orbital, whereas in the acidic solutions, the peak is shifted by -0.3 eV. The emission spectra taken as a function of the GB concentration have been analyzed by means of a modified classical least-squares regression method to obtain the hydration number of the solute. The analysis is successful when the emission spectra have been acquired at the energy of a slightly detuned resonance, giving 28 and 24 as the minimum values for the zwitterionic and protonated GB, respectively. The number of 28 accords with the reported values for the number of water molecules in the first hydration layer of the zwitterion and is greater than that obtained by other experimental techniques. The obtained numbers are used to discuss the hydration structure of GB with the aid of ab initio molecular orbital calculations. The hydration structure of the protonated form of GB is explored for the first time.

Statistical interaction analyses between SARS-CoV-2 main protease and inhibitor N3 by combining molecular dynamics simulation and fragment molecular orbital calculation

A combination of classical molecular dynamics (MD) simulation and ab initio fragment molecular orbital (FMO) calculation was applied to a complex formed between the main protease of the new coronavirus and the inhibitor N3 to calculate interactions within the complex while incorporating structural fluctuations mimicking physiological conditions. Namely, a statistical evaluation of interaction energies between N3 and amino acid residues was performed by processing a thousand of structure samples. It was found that relative importance of each residue is altered by the structural fluctuation. The MD-FMO combination should be promising to simulate protein related systems in a more realistic way.

Proposal of novel inhibitors for vitamin-D receptor: Molecular docking, molecular mechanics and ab initio molecular orbital simulations

The specific binding of active vitamin-D to the vitamin-D receptor (VDR) is closely related to the onset of immunological diseases. To inhibit the binding, various compounds have been developed as potent inhibitors against VDR. Among them, a compound NS-54c, which was developed based on the first VDR antagonist TEI-9647 (25-dehydro-1α-hydroxyvitamin D3-26,23-lactone), was revealed to posse almost 1000-fold improved antagonistic activity over the original TEI-9647. However, the reason for this significant improvement has not been elucidated. In the present study, we investigated the specific interactions between VDR and these inhibitors, using molecular simulations based on molecular docking, molecular mechanics and ab initio fragment molecular orbital calculations. Based on the results simulated, we furthermore proposed novel inhibitors and investigated their binding properties to VDR. The results elucidate that the replacement of propyl group at the 24th site of NS-54c by a phenethyl group can enhance the binding affinity of the inhibitor to VDR. This finding provides useful information for developing novel potent inhibitors against VDR.

Proposal of Potent Inhibitors for a Bacterial Cell Division Protein FtsZ: Molecular Simulations Based on Molecular Docking and ab Initio Molecular Orbital Calculations.

The inhibition of a bacterial cell division protein, filamentous temperature-sensitive Z (FtsZ), prevents the reproduction of Mycobacteria. To propose potent inhibitors of FtsZ, the binding properties of FtsZ with various derivatives of Zantrin ZZ3 were investigated at an electronic level, using molecular simulations. We here employed protein–ligand docking, classical molecular mechanics (MM) optimizations, and ab initio fragment molecular orbital (FMO) calculations. Based on the specific interactions between FtsZ and the derivatives, as determined by FMO calculations, we proposed novel ligands, which can strongly bind to FtsZ and inhibit its aggregations. The introduction of a hydroxyl group into ZZ3 was found to enhance its binding affinity to FtsZ.