Pair Interaction Energies Research Articles

Bioavailability and molecular recognition between secondary metabolites of Euphorbia hirta L. and 5-lipoxygenase using fragment molecular orbital method and pair interaction energy decomposition analysis

Is presented the bioavailability analysis for seven secondary metabolites from Euphorbia hirta L. (Euphorbiaceae). The bioactivity score, the molecular similarity analysis for each secondary metabolite, and the molecular docking 5-LOX/metabolite complex are also presented. For the similarity analysis, it is referenced the structure of allosteric LOX-5 inhibitor 3-acetyl-11-keto-beta-boswellic acid (AKBA). The fragment molecular orbital method (FMO) and pair interaction energy decomposition analysis (PIEDA) were applied to evaluate the interaction energy between secondary metabolites and the 5-LOX active site. Log P values of all the secondary metabolites studied were found to be higher than 5, contrary to what was expected with Lipinski’s rules of five. The reference LOX-5 ligand has a high electrostatic potential similarity with most secondary metabolites studied, with values from 0.667 to 0.730. Both AKBA and metabolites ligands were wedged between the two domains of LOX-5, and the main residues contact were LEU-66, ARG-68, VAL-110, HIS-130, ILE-126, GLN, 129, and LYS-133. The PIEDA analysis showed that stabilization in the 5-LOX active site is mainly dominated by hydrophobic interactions, with values up to -35 Kcal/mol. Due to the low presence of terminal-OH groups, electrostatic origin, and charge transfer interaction energies are also important but have values of less than 20 Kcal/mol.

Synthesis, XRD structural analysis and theoretical studies of a potential inhibitor against rheumatoid arthritis (RA).

This work focused on analyzing the properties of N-(5-nitrothiazol-2-yl)furan-2-carboxamide (C8H5N3O4S, NTFC) as a possible inhibitor of the rheumatoid arthritis process. The synthesis of NTFC was carried out and good-quality crystals were obtained and studied by NMR (1H and 13C), DEPT 135, UV-Vis, IR, MS and single-crystal X-ray diffraction. The structure of NTFC consists of two rings, thiazole and furan, and a central C-N-C(=O)-C segment, which appears to be planar. This central amide segment forms angles of 2.61 (10) and 7.97 (11)° with the planes of the thiazole and furan rings, respectively. The crystal structure of NTFC exhibits N-H...N, N-H...O and C-H...O hydrogen bonds, and C-H...π and π-π interactions that facilitate self-assembly and the formation of hydrogen-bonded dimers, which implies the appearance of R22(8) graph-set motifs in this interaction. The stability of the dimeric unit is complemented by the formation of strong intramolecular C-S...O interactions of chalcogen character, with an S...O distance of 2.6040 (18) Å. Hirshfeld surface (HS) analysis revealed that O...H/H...O interactions were dominant, accounting for 36.8% of the total HS, and that N-H...N interactions were fundamental to the formation of the dimeric structure. The molecular electrostatic potential (MEP) map showed a maximum energy of 46.73 kcal mol-1 and a minimum of -36.06 kcal mol-1. The interaction energies of molecular pairs around NTFC are highest for those interactions linked by N-H hydrogen bonds. The properties of the NTFC ligand as a potential inhibitor of the DHODH (dihydroorotate dehydrogenase) enzyme were evaluated by molecular docking, showing coupling energies very close to those obtained with the control drug for rheumatoid arthritis, i.e. leflunomide.

Quantum chemical calculation dataset for representative protein folds by the fragment molecular orbital method

The function of a biomacromolecule is not only determined by its three-dimensional structure but also by its electronic state. Quantum chemical calculations are promising non-empirical methods available for determining the electronic state of a given structure. In this study, we used the fragment molecular orbital (FMO) method, which applies to biopolymers such as proteins, to provide physicochemical property values on representative structures in the SCOP2 database of protein families, a subset of the Protein Data Bank. Our dataset was constructed by over 5,000 protein structures, including over 200 million inter-fragment interaction energies (IFIEs) and their energy components obtained by pair interaction energy decomposition analysis (PIEDA) using FMO-MP2/6-31 G*. Moreover, three basis sets, 6-31 G*, 6-31 G**, and cc-pVDZ, were used for the FMO calculations of each structure, making it possible to compare the energies obtained with different basis functions for the same fragment pair. The total data size is approximately 6.7 GB. Our dataset will be useful for functional analyses and machine learning based on the physicochemical property values of proteins.

Theoretical Investigation of the structure and Raman scattering properties of Hoogsteen- and Watson-Crick-type Adenine-Thymine base pair

Hoogsteen (HG) and Watson-Crick (WC) adenine–thymine (A-T) base pairs are fundamental to gene expression and genomic stability. Our research applied density functional theory (DFT) calculations to analyze these base pairs, demonstrating that linking them with ribose or deoxyribose and their immersion in solvents markedly enhances the distinctions in their optical properties. DFT results reveal that N···HN hydrogen bonds in both HG and WC pairs exhibit characteristics of both ionic and covalent bonds, playing a crucial role in their stability. While WC base pairs demonstrate stronger orbital interactions, they also experience greater repulsion than HG pairs. This repulsion offsets the positive interactions to a degree, making the interaction energy of WC pairs slightly lower than that of HG pairs. Furthermore, the distinct conformations of these base pairs result in different vibrational modes, suggesting Raman spectroscopy as an effective method for distinguishing between WC and HG base pairs.

An automated calculation pipeline for differential pair interaction energies with molecular force fields using the Tinker Molecular Modeling Package

An automated pipeline for comprehensive calculation of intermolecular interaction energies based on molecular force-fields using the Tinker molecular modelling package is presented. Starting with non-optimized chemically intuitive monomer structures, the pipeline allows the approximation of global minimum energy monomers and dimers, configuration sampling for various monomer–monomer distances, estimation of coordination numbers by molecular dynamics simulations, and the evaluation of differential pair interaction energies. The latter are used to derive Flory–Huggins parameters and isotropic particle–particle repulsions for Dissipative Particle Dynamics (DPD). The computational results for force fields MM3, MMFF94, OPLS-AA and AMOEBA09 are analyzed with Density Functional Theory (DFT) calculations and DPD simulations for a mixture of the non-ionic polyoxyethylene alkyl ether surfactant C10E4 with water to demonstrate the usefulness of the approach.Scientific ContributionTo our knowledge, there is currently no open computational pipeline for differential pair interaction energies at all. This work aims to contribute an (at least academically available, open) approach based on molecular force fields that provides a robust and efficient computational scheme for their automated calculation for small to medium-sized (organic) molecular dimers. The usefulness of the proposed new calculation scheme is demonstrated for the generation of mesoscopic particles with their mutual repulsive interactions.

Modulation of the intermolecular interactions of cucurbit[7]uril with phenylalanine derivatives by the functional groups

Abstract Intermolecular interactions in 1:1 inclusion complexes of cucurbit[7]uril (CB[7]) with phenylalanine derivatives were investigated by density functional theory (B97-D) calculations. For each complex, 2 optimized geometries were found: conformer C in which a guest molecule resided in the center of CB[7], and conformer E where a guest molecule was present at the edge of CB[7]. The order of energy differences between these conformers agreed well with previously reported differences in the affinity of guest molecules for CB[7]. Molecular dynamics simulations of the complexes showed that the guest molecules in CB[7] had different stabilities, and the calculated binding free energies between them also qualitatively agreed with the experimental results. Pair-interaction energy decomposition analyses of the complexes at FMO-MP2/6-31G(d) and aug-cc-pVDZ level of theory were performed using snapshot structures at 500 ns of simulations. The dispersion interaction characterized the interaction, and the order of total interaction energies between the guest molecules and CB[7] was also associated with the experimental results. A significant difference in electrostatic interaction energies was observed in conformer E, which was correlated with the stability of the guest molecules at the edge of CB[7]. The balance between the stabilities of these conformers was correlated with the affinity of guest molecules for CB[7].

(5S)-5-Benzylswainsonines as potent and selective inhibitors of Golgi α-mannosidase II: synthesis, enzyme evaluation and molecular modelling

Development of novel anti-cancer therapeutics based on Golgi α-mannosidase II (GMII) inhibition is considerably impeded by an undesired co-inhibition of lysosomal α-mannosidase leading to severe side-effects. In this contribution, we describe a fully stereoselective synthesis of (5S)-5-[4-(halo)benzyl]swainsonines as highly potent and selective inhibitors of GMII. The synthesis starts from a previously reported aldehyde readily available from l-ribose, and the key features include an intramolecular reductive amination with substrate-controlled stereoselectivity and a late-stage derivatisation of the benzyl group via ipso-substitution. These novel swainsonine analogues were found to be nanomolar inhibitors of the Golgi-type α-mannosidase AMAN-2 (Ki = 23–75 nM) with excellent selectivity (selectivity index = 205–870) over the lysosomal-type Jack bean α-mannosidase. Finally, molecular docking and pKa calculations were performed to provide more insight into the structure of the inhibitor:enzyme complexes, and a pair interaction energy analysis (FMO-PIEDA) was carried out to rationalise the observed potency and selectivity of the inhibitors.

Molecular dynamics study of the thermodynamic properties of triglyceride/methanol mixtures in the presence of cosolvent

Biodiesel is a renewable source of energy that has the potential to replace fossil fuel-based resources. It is produced via the transesterification reaction in which a triglyceride reacts with methanol in the presence of a catalyst. Cosolvents are usually added to the reactants in transesterification to improve the mutual solubility of methanol and triglycerides and to create a single phase. The commonly used cosolvents in transesterification include tetrahydrofuran (THF) and diethyl ether (DEE). Understanding the thermodynamic properties of this system is important in the selection of cosolvent. In this study, molecular dynamics simulations were used to study the mixing behavior between the components of ternary mixtures of triolein/methanol/THF and triolein/methanol/DEE via the application of Flory-Huggins theory of solutions. A simple approach to calculation of the Flory-Huggins interaction parameters is used in which the mixing energy is derived from averaged non-bonded pair interaction energies. Apart from pure triolein, these ternary systems resemble the experimentally studied ternary systems employing various plant-based oils. The binary interaction parameters, Gibbs Free energy and chemical potentials of the components were calculated to study the mixing behavior. Our results show that along the experimental phase boundary the binary interaction parameters remain relatively unchanged with a deviation observed at the highest volume fractions of triolein where the highest binary interactions were observed indicating the possibility of phase separation. The Gibbs energy of mixing for the systems changed from positive to negative as one moves from two phase to single phase part of the ternary system as expected and in agreement with experimental data. The chemical potentials of the ternary mixture components were calculated from the partial derivatives of the Gibbs free energy of mixing. The activities calculated from Flory-Huggins chemical potentials were compared to those calculated using the UNIFAC model. There is good agreement between the two, with both able to predict a single and biphasic mixture. However, disagreements are noted at low and high concentrations of triolein.

Colloidal Stability of PFSA-Ionomer Dispersions. Part I. Single-Ion Electrostatic Interaction Potential Energies.

Charged colloidal particles neutralized by a single counterion are increasingly important for many emerging technologies. Attention here is paid specifically to hydrogen fuel cells and water electrolyzers whose catalyst layers are manufactured from a perfluorinated sulfonic acid polymer (PFSA) suspended in aqueous/alcohol solutions. Partially dissolved PFSA aggregates, known collectively as ionomers, are stabilized by the electrostatic repulsion of overlapping diffuse double layers consisting of only protons dissociated from the suspended polymer. We denote such double layers containing no added electrolyte as "single ion". Size-distribution predictions build upon interparticle interaction potential energies from the Derjaguin-Landau-Verwey-Overbeek (DLVO) formalism. However, when only a single counterion is present in solution, classical DLVO electrostatic potential energies no longer apply. Accordingly, here a new formulation is proposed to describe how single-counterion diffuse double layers interact in colloidal suspensions. Part II (Srivastav, H.; Weber, A. Z.; Radke, C. J. Langmuir 2024 DOI: 10.1021/acs.langmuir.3c03904) of this contribution uses the new single-ion interaction energies to predict aggregated size distributions and the resulting solution pH of PFSA in mixtures of n-propanol and water. A single-counterion diffuse layer cannot reach an electrically neutral concentration far from a charged particle. Consequently, nowhere in the dispersion is the solvent neutral, and the diffuse layer emanating from one particle always experiences the presence of other particles (or walls). Thus, in addition to an intervening interparticle repulsive force, a backside osmotic force is always present. With this new construction, we establish that single-ion repulsive pair interaction energies are much larger than those of classical DLVO electrostatic potentials. The proposed single-ion electrostatic pair potential governs dramatic new dispersion behavior, including dispersions that are stable at a low volume fraction but unstable at a high volume fraction and finite volume-fraction dispersions that are unstable with fine particles but stable with coarse particles. The proposed single-counterion electrostatic pair potential provides a general expression for predicting colloidal behavior for any charged particle dispersion in ionizing solvents with no added electrolyte.

The Pivotal Distinction between Antagonists' and Agonists' Binding into Dopamine D4 Receptor-MD and FMO/PIEDA Studies.

The dopamine D4 receptor (D4R) is a promising therapeutic target in widespread diseases, and the search for novel agonists and antagonists appears to be clinically relevant. The mechanism of binding to the receptor (R) for antagonists and agonists varies. In the present study, we conducted an in-depth computational study, teasing out key similarities and differences in binding modes, complex dynamics, and binding energies for D4R agonists and antagonists. The dynamic network method was applied to investigate the communication paths between the ligand (L) and G-protein binding site (GBS) of human D4R. Finally, the fragment molecular orbitals with pair interaction energy decomposition analysis (FMO/PIEDA) scheme was used to estimate the binding energies of L-R complexes. We found that a strong salt bridge with D3.32 initiates the inhibition of the dopamine D4 receptor. This interaction also occurs in the binding of agonists, but the change in the receptor conformation to the active state starts with interaction with cysteine C3.36. Such a mechanism may arise in the case of agonists unable to form a hydrogen bond with the serine S5.46, considered, so far, to be crucial in the activation of GPCRs. The energy calculations using the FMO/PIEDA method indicate that antagonists show higher residue occupancy of the receptor binding site than agonists, suggesting they could form relatively more stable complexes. Additionally, antagonists were characterized by repulsive interactions with S5.46 distinguishing them from agonists.

Solvation dynamics on the diffusion timescale elucidated using energy-represented dynamics theory.

Photoexcitation of a solute alters the solute-solvent interaction, resulting in the nonequilibrium relaxation of the solvation structure, often called a dynamic Stokes shift or solvation dynamics. Thanks to the local nature of the solute-solvent interaction, the characteristics of the local solvent environment dissolving the solute can be captured by the observation of this process. Recently, we derived the energy-represented Smoluchowski-Vlasov (ERSV) equation, a diffusion equation for molecular liquids, which can be used to analyze the solvation dynamics on the diffusion timescale. This equation expresses the time development for the solvent distribution on the solute-solvent pair interaction energy (energy coordinate). Since the energy coordinate can effectively treat the solvent flexibility in addition to the position and orientation, the ERSV equation can be utilized in various solvent systems. Here, we apply the ERSV equation to the solvation dynamics of 6-propionyl-2-dimethylamino naphthalene (Prodan) in water and different alcohol solvents (methanol, ethanol, and 1-propanol) for clarifying the differences of the relaxation processes among these solvents. Prodan is a solvent-sensitive fluorescent probe and is thus widely utilized for investigating heterogeneous environments. On the long timescale, the ERSV equation satisfactorily reproduces the relaxation time correlation functions obtained from the molecular dynamics (MD) simulations for these solvents. We reveal that the relaxation time coefficient on the diffusion timescale linearly correlates with the inverse of the translational diffusion coefficients for the alcohol solvents because of the Prodan-solvent energy distributions among the alcohols. In the case of water, the time coefficient deviates from the linear relationship for the alcohols due to the difference in the extent of importance of the collective motion between the water and alcohol solvents.

Asymmetric Cross Couplings of Trifluoromethyl Radical to Vinylarenes with N‐Hydroxy‐oxazinediones and Subsequent Aerobic Oxidative Homocoupling of 2‐Naphthols Catalysed by Chiral Vanadyl Complexes

AbstractAsymmetric three‐component, 1,2‐aminoxy‐trifluoromethylation of styrenes with N‐hydroxy‐1,3‐benz/naphthoxazine‐2,4‐diones (i. e., N‐OH‐(B/Np)OxzOn) catalysed by chiral vanadyl complexes derived from N‐salicylidene‐L‐t‐leucinate were explored. Among 14 different solvents and 13 different catalysts screened, the best reaction scenarios were in 2‐propanol with 3‐(2,5‐dimethyl)phenyl‐5‐bromo (DMP), or 3‐t‐butyl‐5‐bromo substituted catalysts that led to the corresponding complementary (R)‐ and (S)‐products with potential biological activities in 45–91% yields and up to 85 and 75% ee, respectively. Further optimisation with the DMP catalyst led to the best combination of 3‐halo/3,5‐dihalo‐styrenes with 6‐/7‐Br−N−OH‐(B/Np)OxzOn as the trapping agents. The corresponding eight different products were isolated in 52–75% yields with ees in a range of 88–93% (R). Based on Density Functional Theory (DFT) calculations with conformational searches, the origin of enantiocontrol and the working mechanism were proposed by resorting to a bidentate‐chelation between the amide or carbamate C=O group and N−OH group in the trapping agent to the vanadyl center followed by asymmetric benzylic radical trapping in an SH2 fashion. Subsequent Fragment Molecular Orbital (FMO)/Pair Interaction Energy Decomposition Analysis (PIEDA) calculations with the DMP catalyst were carried out to rationalize the extent of asymmetric induction. One representative product derived from p‐methyl‐styrene and NpOxzOn was hydrolyzed in basic MeOH with decarboxylation to unmask its carbamate moiety. The resulting chiral (R)‐N‐benzoxy‐3‐hydroxy‐2‐naphthamide was subjected to aerobic, oxidative homo‐coupling catalysed by the DMP catalyst in CCl4. The corresponding 2,2‐binaphthol product was isolated in 90% (brsm) yield with nearly complete diastereo‐control at the created (M)‐axial chirality, allowing for sequential, bi‐functional asymmetric cross‐coupling applications.

Structural and computational insights into two trimethylenedipyridine co-crystals: Inputs from X-ray diffraction, Hirshfeld surface, PIXEL, QTAIM and NCI plots

Two trimethylenedipyridine co-crystals, [(TMDP)·(H2OBA)] (1) and [(TMDP)·(SUC)] (2) [TMDP = 4, 4′-trimethylenedipyridine, H2OBA = 4,4′-oxybis(benzoic acid), and SUC = succinic acid) were designed, synthesized and their single crystals were grown by slow evaporation technique. The grown crystals were characterized by elemental analysis and UV–Vis spectroscopic technique, and the structures of the grown crystals were elucidated using single-crystal X-ray diffraction analysis. Supramolecular assemblies of co-crystal (1) are stabilized through several intermolecular hydrogen bonds such as O‒H···N, C‒H···O, C‒H···π, as well as π···π interactions whereas for co-crystal (2) only intramolecular hydrogen bonding interaction, O‒H···N is responsible for stabilization of supramolecular network. Hirshfeld surfaces were used to gain additional insight into non-covalent interactions in molecular crystals, and 2D fingerprint plots provided a quantitative analysis of different non-covalent interactions in the crystal structures. The interaction energies of the molecular pairs, as well as the lattice energies of the crystal structures, have been studied using the PIXEL method. The nature and strength of the non-covalent interactions at their (3, –1) bond critical points (BCPs) have been explored using Bader's quantum theory of “Atoms in Molecules” (QTAIM). The non-covalent interactions were further characterized through the NCI plots.

Improving the accuracy of the FMO binding affinity prediction of ligand-receptor complexes containing metals.

Polarization and charge transfer strongly characterize the ligand-receptor interaction when metal atoms are present, as for the Au(I)-biscarbene/DNA G-quadruplex complexes. In a previous work (J Comput Aided Mol Des2022, 36, 851-866) we used the ab initio FMO2 method at the RI-MP2/6-31G* level of theory with the PCM [1] solvation approach to calculate the binding energy (ΔEFMO) of two Au(I)-biscarbene derivatives, [Au(9-methylcaffein-8-ylidene)2]+ and [Au(1,3-dimethylbenzimidazole-2-ylidene)2]+, able to interact with DNA G-quadruplex motif. We found that ΔEFMO and ligand-receptor pair interaction energies (EINT) show very large negative values making the direct comparison with experimental data difficult and related this issue to the overestimation of the embedded charge transfer energy between fragments containing metal atoms. In this work, to improve the accuracy of the FMO method for predicting the binding affinity of metal-based ligands interacting with DNA G-quadruplex (Gq), we assess the effect of the following computational features: (i) the electron correlation, considering the Hartree-Fock (HF) and a post-HF method, namely RI-MP2; (ii) the two (FMO2) and three-body (FMO3) approaches; (iii) the basis set size (polarization functions and double-ζ vs. triple-ζ) and (iv) the embedding electrostatic potential (ESP). Moreover, the partial screening method was systematically adopted to simulate the solvent screening effect for each calculation. We found that the use of the ESP computed using the screened point charges for all atoms (ESP-SPTC) has a critical impact on the accuracy of both ΔEFMO and EINT, eliminating the overestimation of charge transfer energy and leading to energy values with magnitude comparable with typical experimental binding energies. With this computational approach, EINT values describe the binding efficiency of metal-based binders to DNA Gq more accurately than ΔEFMO. Therefore, to study the binding process of metal containing systems with the FMO method, the adoption of partial screening solvent method combined with ESP-SPCT should be considered. This computational protocol is suggested for FMO calculations on biological systems containing metals, especially when the adoption of the default ESP treatment leads to questionable results.

Base pairs with 5-chloroorotic acid and comparison with the natural nucleobase. Structural and spectroscopic study, and three suggested antiviral modified nucleosides

A structural and spectroscopic study of 5-chloroorotic acid (5-ClOA) biomolecule was carried out by IR and FT-Raman and the results obtained were compared to those achieved in 5-fluoroorotic acid and 5-aminoorotic acid compounds. The structures of all possible tautomeric forms were determined using DFT and MP2 methods. To know the tautomer form present in the solid state, the crystal unit cell was optimized through dimer and tetramer forms in several tautomeric forms. The keto form was confirmed through an accurate assignment of all the bands. For this purpose, an additional improvement in the theoretical spectra was carried out using linear scaling equations (LSE) and polynomic equations (PSE) deduced from uracil molecule. Base pairs with uracil, thymine and cytosine nucleobases were optimized and compared to the natural Watson-Crick (WC) pairs. The counterpoise (CP) corrected interaction energies of the base pairs were also calculated. Three nucleosides were optimized based on 5-ClOA as nucleobase, and their corresponding WC pairs with adenosine. These modified nucleosides were inserted in DNA:DNA and RNA:RNA microhelices, which were optimized. The position of the -COOH group in the uracil ring of these microhelices interrupts the DNA/RNA helix formation. Because of the special characteristic of these molecules they can be used as antiviral drugs. Communicated by Ramaswamy H. Sarma

Comparative study of interaction energies between αIIbβ3 integrin and the peptidic, peptidomimetic and non-peptidic ligands by quantum mechanics FMO-PIEDA calculations

Integrins belong to a family of cell adhesion receptors. To better understand an adhesion mechanism of integrins, fragmented molecular orbital (FMO) method with pair interaction energy decomposition analysis (PIEDA) was applied for integrin:ligand complexes. Interaction energies were evaluated between the amino acid residues including Mg2+ and Ca2+ ions at ligand-binding site of αIIbβ3 integrin and two peptide chains with the Ala-Gly-Asp (AGD)- and the Arg-Gly-Asp (RGD)-binding motifs, a cyclic peptide (eptifibatide), peptidomimetic ligands (tirofiban and L-739758) and poly(l-lactic acid) chain (PLA). The results indicate that Mg2+ and Ca2+ ions together with Asp224A, Asn215B, Asp159A and Lys125B of αIIbβ3 are the most important residues for a binding of the peptidic ligands while for the peptidomimetic ligands and PLA, interactions with Ca2+ ions are less significant than those with amino acid residues of αIIbβ3. For all complexes, a dominant part of interaction energy comes from electrostatic interactions. New developed antagonists of αIIbβ3 should mimic not only the interactions of the RGD motif but also the interactions of the backbone of a longer peptidic sequence (RGDV or AGDV) with the focus on the interactions of the antagonists with the ADMIDAS Ca2+ ion. An interaction pattern predicted for PLA was compared with the native peptidic ligands.

COMBINATION EFFECT OF TRANSITION METAL IMPURITIES ON THE OXYGEN VACANCY FORMATION ENERGETICS IN TIO2

The combination effect of substitutional impurities of group IVB-VIB transition metals on the oxygen vacancy formation energy in titania with rutile structure was studied by the projector augmented-wave method within the density functional theory. The pair interaction energy of impurity atoms was estimated depending on the interatomic distance. It was shown that the interaction in the Zr + Zr, Hf+Hf and Nb + Ta pairs leads to the energy preference of their orientation along the (100) direction at a distance of the lattice parameter a. The Mo + Mo and Nb + Mo pairs prefer to orient along the [001] direction at a distance of the lattice parameter c. If the impurity atoms are farther than the third neighbors, then their interaction can be neglected. It was found that the change in the formation energy of the oxygen vacancy due to doping with several impurities can be estimated as the sum of the energy changes due to single impurity divided by a coefficient whose value depends on the mutual arrangement of the impurity atoms.

Dynamical Interaction Analysis of Proteins by a Random Forest-Fragment Molecular Orbital (RF-FMO) Method and Application to Src Tyrosine Kinase

Abstract Identifying key intermolecular (amino acid) interactions is crucial for understanding intrinsic protein functions. In this study, we established an efficient method for discovering key interactions by combining the random forest (RF) method, a machine learning algorithm, and an interaction analysis based on the fragment molecular orbital (FMO) method. We applied this method to Src tyrosine kinase and verified its efficacy. We performed molecular dynamics simulations of both the open and closed forms of Src and selected 50 snapshots for each. Then, pair interaction energy (PIE) or inter-fragment interaction energy (IFIE) analyses were performed using FMO with the van der Waals (vdW)-corrected density functional tight-binding (DFTB) method. Among the 100 × 34453 data sets, we can identify the key amino acid pair regulating the open-close transition. This is consistent with the experimental and theoretical results, indicating the usefulness of the presented method. In contrast to the conventional FMO PIE interaction analysis, in the proposed method, the protein dynamics can be partially included using hundreds of trajectory data.

The FMO2 analysis of the ligand-receptor binding energy: the Biscarbene-Gold(I)/DNA G-Quadruplex case study.

In this work, the ab initio fragment molecular orbital (FMO) method was applied to calculate and analyze the binding energy of two biscarbene-Au(I) derivatives, [Au(9-methylcaffein-8-ylidene)2]+ and [Au(1,3-dimethylbenzimidazol-2-ylidene)2]+, to the DNA G-Quadruplex structure. The FMO2 binding energy considers the ligand-receptor complex as well as the isolated forms of energy-minimum state of ligand and receptor, providing a better description of ligand-receptor affinity compared with simple pair interaction energies (PIE). Our results highlight important features of the binding process of biscarbene-Au(I) derivatives to DNA G-Quadruplex, indicating that the total deformation-polarization energy and desolvation penalty of the ligands are the main terms destabilizing the binding. The pair interaction energy decomposition analysis (PIEDA) between ligand and nucleobases suggest that the main interaction terms are electrostatic and charge-transfer energies supporting the hypothesis that Au(I) ion can be involved in π-cation interactions further stabilizing the ligand-receptor complex. Moreover, the presence of polar groups on the carbene ring, as C = O, can improve the charge-transfer interaction with K+ ion. These findings can be employed to design new powerful biscarbene-Au(I) DNA-G quadruplex binders as promising anticancer drugs. The procedure described in this work can be applied to investigate any ligand-receptor system and is particularly useful when the binding process is strongly characterized by polarization, charge-transfer and dispersion interactions, properly evaluated by ab initio methods.

Investigation on the morphology and the permeability of biomimetic cellulose triacetate (CTA) impregnated membranes (IM): In-situ synchrotron imaging, experimental and computational studies

The goal of the present study is to ascertain the controlled permeability of the biomimetic cellulose triacetate (CTA) membranes at different temperatures and salt concentrations by investigating the electrical oscillatory behaviour across the impregnated membranes (IM). The novel biomimetic CTA membranes were infused with a capric fatty acid to induce the electrical oscillatory behavior, and hence, to ensure the controlled permeability. In-situ synchrotron-based X-ray tomography (SR-μCT) at BioMedical Imaging and Therapy (BMIT) Beamline at the Canadian Light Source (CLS) was used to evaluate the main impregnated membrane morphology compared to neat CTA to ensure the fatty acid penetration inside membrane pores along membrane matrices. This study has revealed changes in phase transition temperatures of the impregnated CTA membrane at the melting temperature of the fatty acid. The pulsations of measured voltages were observed to be related to changes in the KCl concentration in the vicinity of the Ag/AgCl electrode. In this study, amplitudes and frequencies of voltage pulsations were dependent on the temperature and concentration of the KCl solution to control the permeability of the biomimetic membrane membranes. Increasing the KCl concentration led to a higher frequency of oscillation which reflects a higher permeability. In addition, no mechanical stirring or disturbance of the system was required for the electrical oscillatory phenomenon to occur. Nevertheless, for the average waveforms, the peak-to-peak value obtained was doubled when stirring was performed, while for the higher amplitude waveforms, the amplitude increased by 5 times. In addition, interactions at the molecular level between water molecules and the fragments of infused membranes at different temperatures and their effect on controlling permeability was investigated using pair interaction energy decomposition analysis (PIEDA) as part of the fragment molecular orbital (FMO) method's framework. Those results opened new frontiers for facilitation and regulation of active transport and permeability through biomimetic smart membranes for a variety of biomedical and drug delivery applications.