Journal of Theoretical and Computational Chemistry

The misfolding and aggregation of amyloid-$\beta$ (A$\beta )$ peptides into amyloid fibrils is regarded as one of the possible causes of Alzheimer’s disease (AD). Aromatic interactions (i.e. $\pi$–$\pi$ interactions) between tanshinone drugs extracted from Chinese herb Salvia Miltiorrhiza (SM) and aromatic residues of A$\beta$ peptides have been shown to prevent further growth of amyloid aggregates. In this work, the effects of isomerization, complexation and polarity of environment on the strength of $\pi$–$\pi$ stacking interactions of tanshinone I (TS1) and isotanshinone I (IS1), as the two diterpenoid quinones in the SM herb, and their complexes with Mg${}^{2+}$ cation, IS1-Mg${}^{2+}$ and TS1-Mg${}^{2+}$, with phenylalanine (PHE), as an aromatic amino acid in A$\beta$ structure have been investigated using the quantum mechanical calculations in the gas-phase, ether, acetone, DMSO, and water solvent. Molecular electrostatic potential (MEP), which are used to predict the nucleophile active sites, electron densities calculated at the bond critical points (${\rho }_{\mathrm{\text{BCP}}})$ and ring critical points (${\rho }_{\mathrm{\text{RCP}}})$ by the atoms in molecules (AIM) method and the donor–acceptor interaction energies ($E^2)$ calculated using the natural bond orbital (NBO) method were used to investigate the interplay between $\pi$–$\pi$ stacking and complexation. The results show that the IS1/TS1-Mg${}^{2+}$ compounds have a more protective role compared to TS1/IS1-Mg${}^{2+}$ compounds due to the stronger interaction with PHE of A$\beta$ in antiaggregation for further development of A$\beta$ inhibitors to prevent and disaggregate amyloid formation. Complexation with Mg${}^{2+}$ increases the interaction diterpenoid drugs with PHE and makes notable changes in structural and electronic properties of diterpenoids. Also, the interactions between diterpenoid and PHE in less polar environment are more than other environments. Low-polarity environments have the best mimics of the A$\beta$ binding site.

A dual-level quantum chemical calculations have been carried out on the initiation of night-time degradation of 2-chloroethyl ethyl ether (CH₃CH₂OCH₂CH₂Cl) via H-abstraction by NO₃ radical. Within the scope of density functional theory, the electronic structure of all the species involved in the titled reaction has been optimized at M06-2X functional along with 6-31$+$G(d,p) basis set. A higher level of couple cluster CCSD(T) method in conjunction with 6-311$++$G(d,p) basis set has been used for the refined energy of the species. All minima and saddle states involved in the reaction channel have been characterized on the potential energy surface (PES). From PES, it is confirmed that H-abstraction from methylene (–CH₂–) of ethyl (CH₃CH₂–) part of CH₃CH₂OCH₂CH₂Cl follows the minimum energy path. The rate constants (individual and overall) of the titled reaction are obtained using Canonical Transition State Theory (CTST) over the temperature range of 250–350K. The atmospheric lifetime and radiative efficiency of the titled molecule have also been estimated, amounting to 0.23 years and 0.024 years, respectively. The Global Warming Potentials of the 2-chloroethyl ethyl ether in 20 years, 100 years and 500 years time horizon were found to be 0.13, 0.04 and 0.01, respectively.

Nowadays antibody engineering is an important approach in the design and manufacture of therapeutic and diagnostic antibodies. The study of interactions between antibodies and antigens is the critical step in the design of antibodies with desirable properties. Computational docking is a useful tool for structural characterization of bimolecular interactions. Docking is the process of predicting bound conformations and binding enthalpy of antibody–antigen complexes. In this study, the three-dimensional structures of two ribosome displayed-selected scFv antibodies were constructed by Kotai Antibody Builder. By using ClusPro 2.0 web server, the ESAT-6 antigen (a tuberculosis-specific antigen) structure was docked to both scFv models to obtain the structures of the binding complexes and molecular dynamics (MD) simulations were performed using GROMACS 4.5.3 package. By analyzing of the ESAT-scFv complexes, important amino acids involved in antigen–antibody interactions were identified which were Asn164 in VL3, Ser164 in VL7 and Asn55 in VH7. All three amino acids belonged to the CDRs. In conclusion, results achieved from this bioinformatics study can help in the design and development of novel antibodies with improved affinities for tuberculosis diagnosis.

Mechanisms of decomposition reaction of thymine cation radicals (T${}^{+•}$), 1-methyl substituted T${}^{+•}$ (1-MeT${}^{+•}$), and 1,3-dimethyl substituted T${}^{+•}$ (1,3-Me₂T${}^{+•}$) generated by ionizing radiation or one-electron oxidation to thymine, 1-methylthymine and 1,3-dimethylthymine in aqueous solution have been investigated by theoretical calculations. Seven reaction paths including H₂O or OH${}^{-}$ addition, and deprotonation were considered. The most likely reaction for T${}^{+•}$ decomposition is N1 deprotonation forming T(-N₁H)${}^{•}$. When N1 hydrogen is replaced by methyl, T${}^{+•}$ would deprotonate from C5 methyl group generating 1-methyl substituted UCH${}_2^{•}$ in neutral solution, and reaction with OH${}^{-}$ producing 1-methyl substituted T6OH${}^{•}$ in basic solution. When N1 and N3 hydrogens are both replaced by methyl, T${}^{+•}$ decomposition reaction is similar to 1-MeT${}^{+•}$, indicating that N3 hydrogen barely influences the subsequent reaction of 1-MeT${}^{+•}$. These results can provide theoretical support for experimental observations.

It has been reported that short glucagon-like peptide-1 (sGLP-1), one of glucagon-like peptide 1 (GLP-1) analogues, has the same effect in treating type 2 diabetes mellitus (T2DM) as GLP-1 with increased half-life in human body. Although the high-resolution structure of complex of GLP-1 and its receptor has been achieved, the relationship between the structure of GLP-1 before recognition and its final function is still not clear. As for sGLP-1, few studies attempt to investigate the influences of different conditions on its structure. In present paper, molecular dynamics simulations were applied to explore molecular details of sGLP-1 under various environments. The results demonstrated that in low pH value solvent, the additional helical residue of Pro6 and the flexible N-terminal cannot keep $\alpha$ helix biological conformation. At pH 3, the structure has undergone significant changes, resulting in the shortest helical length. Further studies showed that protonation states of Glu21 mainly determined the secondary structure of sGLP-1 when pH values increased from 3 to 7. Interestingly, with ions concentration varying from 0.18% to 0.72%, the fluctuating trend of backbone RMSDs is consistent with that of $\alpha$ helix structure of sGLP-1. The structure of sGLP-1 had less helix content and became more flexible when temperatures increased in the range from 305K to 320K. Meanwhile, in mixtures of water and 2,2,2-trifluoroethanol (TFE) sGLP-1 showed a rigid structure with an additional helical residue (Pro6) at the N-terminal of original helix content.

Molecular dynamics (MD) simulations were carried out to study the polymer-bonded explosives (PBXs) where the explosive base was the well-known high energy co-crystal compound, 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexazaisowurtzitane/2,4,6-trinitrotoluene (CL-20/TNT), and the polymer binders were fluorine rubber (F${}_{2311})$, fluorine resin (F${}_{2314})$, polyvinyl acetate (PVAc) and polystyrene (PS), respectively. The binding energies, pair correlation functions (PCFs) and mechanical properties of the PBXs were reported. According to our theoretical results of binding energies, the compatibility of the PBXs is predicted to be in the following order: CL-20/TNT/PVAc$>$ CL-20/TNT/F${}_{2311}$ $>$ CL-20/TNT/PS $>$ CL-20/TNT/F${}_{2314}$. The binding energies of the PBXs on three crystalline surfaces, (100), (001), (010), of the CL-20/TNT co-crystal were also compared: CL-20/TNT(100)$>$CL-20/TNT(001)$>$CL-20/TNT(010) for F${}_{2311}$, F${}_{2314}$, and PS; CL-20/TNT(001)$>$CL-20/TNT(100)$>$CL-20/TNT(010) for PVAc. The PCF analysis reveals that there exist H-bonds between H and O, F, and N atoms on all three interfaces and among all H-bonds, N H-bond has the fewest number. For the CL-20/TNT co-crystal, the moduli can be reduced by adding a small amount of the polymer binders but the ductility can be prolonged only by F${}_{2311}$ and F${}_{2314}$.

In this work, we theoretically investigate the properties of excited state process for a novel salicylidene sal-3,4-benzophen (Sal-3,4-B) system, which contains two intramolecular hydrogen bonds (O1-H2$\cdots$N3 and O4-H5$\cdots$N6). Based on the density functional theory (DFT) and time-dependent DFT (TDDFT) methods, we find these two hydrogen bonds should be strengthened in the S₁ state, while the O4-H5$\cdots$N6 one could be largely affected upon the excitation process. Analyses about infrared (IR) vibrational spectra about hydrogen bond moieties also confirm this viewpoint. Frontier molecular orbitals (MOs) depict the nature of electronic excited state and support the excited state intramolecular proton transfer (ESIPT) reaction.Two kinds of stepwise potential energy curves of Sal-3,4-B in the S₁ state demonstrate that only one proton could be transferred. Also based on constructing potential energy curves, the synergetic situation could be eliminated. Due to the specific ESIPT mechanism for Sal-3,4-B, we successfully explain the previous experiment and provide a reasonable attribution to the second emission peak of experiment.

Quantitative structure-activity relationship (QSAR) has been a technique to study the relationship between chemical structures and properties, and variable selection is an important problem for finding the informative variables and building reliable models. A variable selection method based on variable stability is proposed and used for selecting the informative descriptors in the QSAR model of inhibitors. In the method, a series of models are built by leave-one-out cross validation (LOOCV), and variable stability is defined as the ratio of the absolute mean value and standard deviation of the regression coefficients in the models for a descriptor. Therefore, the descriptors with larger stabilities are more informative to the model. To further enhance the difference among the descriptors, an exponential parameter is used to modify the standard deviation. The results show that 13 descriptors are selected as informative ones from 1217 descriptors for the QSAR model of inhibitors. An effective prediction model can be constructed by them.

Phosphorus mononitride (PN) shows some interesting chemistry due to its low dissociation energy (compared to N₂) and small dipole moment (zero dipole moment for N₂). In this work, a reaction between HSi ($X{}^2\mathrm{\Pi }$) and PN ($X{}^1{\mathrm{\Sigma }}^{+}$) has been studied using various computational methods. Analysis of the doublet surface of the $\mathrm{\text{HSi}}+\mathrm{\text{PN}}$ reaction indicates that the reaction is exothermic in nature leading to the formation of various products. In view of the barrierless association of the reactants and exothermic nature for the product formation, it is suggested that species like HPNSi, cyclic-SiN(H)P (these two most stable isomers have phosphazo linkage) and HSiNP (third most stable isomer has phosphdiazo linkage) can possibly be detected in the interstellar medium. In view of the potential applications of phosphazo compounds in amide synthesis and pervasive nature of amide linkages in the nature, possible interstellar prebiotic applications can be advocated for these compounds.

Currently, there is increasing interest in the potential of malaria inhibitors in Plasmodium falciparum activity. In this work, is propose a possible alternative to classifying 154 antimalarials, with P. falciparum activity. These antimalarials were synthesized by the Chibale’s group (http://www.kellychibaleresearch.uct.ac.za/), with the goal of finding new insights on the binding pocket of the protein kinase PfPK5, PfPK7, PfCDPK1, PfCDPK4, PfMAP1, and PfPK6 of the malaria parasite. However, there is only information about crystallography of PfPK5 and PfPK7. The protein kinases PfCDPK1, PfCDPK4, PfMAP1, and PfPK6 were modeled using molecular homology. The validation used shows that our homology models can be an alternative for the protein kinases from P. falciparum, unknown today. The antimalarials were classified by taking into account the interactions in the hinge zone. These ligands bind to the kinase through the formation of one of two hydrogen bonds, with the backbone residues of the hinge region connecting the kinase N- and C-terminal loops. These interactions were supported by a reactivity chemistry analysis, using global chemical reactivity descriptors such as chemical potential, hardness, softness, electrophilicity, and the Fukui functions as local reactivity descriptors, within the Density Functional Theory (DFT) context.

The unimolecular dissociation rate constants of ethylene glycol were examined using the MP2/6-311$++$G(d,p) method based on the Rice–Ramsperger–Kassel–Marcus (RRKM) theory. The effect of anharmonicity on the dissociation rate constants was evaluated at 500–4000K temperatures of the canonical system and 25,182–50,235cm${}^{-1}$ total energies of the microcanonical system. The comparison of the results showed that the H₂O elimination reaction played a critical role in the decomposition processes of ethylene glycol. The results of the rate constant calculations indicated that the H₂O elimination reaction dominated at low temperatures, whereas the direct C–C bond dissociation reaction (CH₂OHCH₂OH $\to$ CH₂OH$+$CH₂OH) dominated at high temperatures. For channel 1, CH₂OH$+$CH₂OH, the anharmonic effect of the canonical system was not observed, while it became more obvious with the increasing total energies in the microcanonical system. For channels 2–5, CH₃CHO$+$H₂O, CH₂CHOH$+$H₂O, CH₃OH$+$CHOH, and CH₂OHCHO$+$H₂, the anharmonic effect of canonical and microcanonical systems became more obvious with increasing temperatures and total energies. The comparison showed that, for channels 1 and 4, C–C bond dissociation and the anharmonic effect of the microcanonical system were more evident, whereas the anharmonic effect of the canonical system was more predominant for channels 2 (CH₃CHO$+$H₂O), 3 (CH₂CHOH$+$H₂O), and 5 (CH₂OHCHO$+$H₂).