Ab initio calculations on the thermodynamic properties of azaborospiropentanes

Following our recent studies of the thermodynamic properties of azaspiropentane and borospiropentane, in consideration of their usefulness as new potential high energy materials, we follow up with ab initio calculations on the thermodynamic properties of azaborospiropentanes. Properties reported in this study include optimized structural parameters, vibrational frequencies, enthalpies of formation, specific enthalpies of combustion, proton affinities, and hydride affinities. Our results indicate that azatriborospiropentane gives off most energy when combusted, as evidenced by its specific enthalpy of combustion of about −52 kJ per gram. Figure Optimized geometry for R-azatriborospiropentane (10) Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Application of the PM6 method to modeling the solid state

The applicability of the recently developed PM6 method for modeling various properties of a wide range of organic and inorganic crystalline solids has been investigated. Although the geometries of most systems examined were reproduced with good accuracy, severe errors were found in the predicted structures of a small number of solids. The origin of these errors was investigated, and a strategy for improving the method proposed. Figure Detail of Structure of Dihydrogen Phosphate in KH₂PO₄ (upper pair) and in (CH₃)₄NH₂PO₄. (Footnote): X-ray structures on left, PM6 structure on right. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of various benzodiazepine analogues of γ-secretase inhibitors

A 3D QSAR analysis has been performed on a series of 67 benzodiazepine analogues reported as γ-secretase inhibitors using molecular field analysis (MFA), with G/PLS to predict steric and electrostatic molecular field interaction for the activity. The MFA study was carried out using a training set of 54 compounds. The predictive ability of model developed was assessed using a test set of 13 compounds ( as high as 0.729). The analyzed MFA model has demonstrated a good fit, having r² value of 0.858 and cross validated coefficient, value as 0.790. The analysis of the best MFA model provided insight into possible modification of the molecules for better activity.   Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Ligation of Aza bases to the AgF<Subscript>2</Subscript> molecule: a theoretical study

We have analyzed the electronic structure and chemical bonding for molecular adducts of the Ag(II)F₂ molecule with various aza Lewis bases including ammonia, nitriles, secondary amines, and their derivatives exhibiting various degrees of fluorination. Density functional theory calculations indicate that a progressive shift occurs of the spin density from the Ag center towards the coordinating nitrogen atoms of aza ligands, as the ligation energy increases. Chemistry of Ag(II) might be extended with little effort beyond the known aza connections, to include nitriles, perfluorinated nitriles and perfluorinated amines. Figure Properties of a variety of novel adducts of the AgF₂ molecule with two aza bases (L), possible precursors of the AgF₂L₂ extended solids, were assessed by the DFT calculations Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. This work is dedicated to memory of Wojciech Ochmański, unforgettable person, good-hearted man, whose craftsmanship in work was second-to-none.     

Ab initio multireference study of Hetero-Diels-Alder reaction of buta-1,3-diene with alkyl glyoxylates

Hetero-Diels-Alder (HDA) reaction of methyl glyoxylate with buta-1,3-diene has been investigated using multireference methods (complete active space SCF and multi-reference perturbation theory) and compared with several single-reference methods (including DFT) often used in calculations of catalysed [4+2] cycloadditions. Concerted and stepwise mechanisms, found in the literature, are compared. It is shown, that the stepwise mechanism may be a result of choosing unbalanced active space. Such choice leads to very close singlet and triplet states in the intermediate geometry - an artificial effect, that disappears if properly balanced active space is used (here, we use active space of 12 orbitals and 12 electrons). Conclusions concerning the mechanism and usefulness of the applied methodology are drawn, which might be important for theoretical investigation of stereoselectivity and specificity of catalysts for the HDA reaction. Figure Hetero-Diels-Alder reaction of alkyl glyoxylates with buta-1,3-diene, investigated using multi- and single-reference ab initio methods Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Theoretical study of spin-spin coupling across the hydrogen (O-H⋯N) bond in adenosine derivatives

The study of spin-spin coupling constants across hydrogen bond provides useful information about configuration of complexes. The interesting case of such interactions was observed as a coupling across an intramolecular hydrogen bond in 8-bromo-2′,3′-O-isopropylideneadenosine between the -CH₂OH (at 5″ proton) group and the nitrogen atom of adenine. In this paper we report theoretical investigations on the ^4h J _NH coupling across the H″-C-O-H···N hydrogen bond in adenosine derivatives in various solvent models. Figure Coupling constants in 8-bromo-2′,3′-O-isopropylideneadenosine Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Formation and isomerization of dicyclopenta[de,mn]anthracene. Electronic Structure Study

The formation of dicyclopenta[de,mn]anthracene (P1) and its isomerization into dicyclopenta[jk,mn]phenanthrene (P3) was investigated using density functional theory. It was shown that P1 is formed from 1,4-diethynilanthracene, but due to its instability, it undergoes further transformation. This transformation involves rearrangements of some hydrogen atoms and ring contraction/ring expansion process, yielding as a final product the isomer P3. The energies of activation for the P1→P3 intraconversion show that this reaction is competitive to the other, previously investigated isomerization of P1 into dicyclopenta[de,kl]anthracene (P2). In addition, our investigation shows that the formation of P3 from P1 is energetically more favorable than the formation of P3 from P2. Thus, the presence of the isomer P3 in the reaction mixtures could also be caused by the isomerization of the very unstable isomer P1. Figure Isomerization of 1,4-diethynilanthracene to dicyclopenta[jk,mn]phenanthrene via dicyclopenta[de,mn]anthracene Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Pharmacophore mapping of a series of pyrrolopyrimidines,indolopyrimidines and their congeners as multidrug-resistance-associated protein (MRP1) modulators

Pharmacophore mapping studies were undertaken for a series of molecules belonging to pyrrolopyrimidines, indolopyrimidines and their congeners as multidrug resistance-associated protein (MRP1) modulators. A five-point pharmacophore with two hydrogen bond acceptors (A), one lipophilic/hydrophobic group (H), one positive ionic feature (P) and one aromatic ring (R) as pharmacophoric features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of r ² = 0.799 for training set molecules. The model generated showed excellent predictive power, with a correlation coefficient Q ² = 0.679 for an external test set of 20 molecules. The pharmacophore was further validated using four structurally diverse compounds with MRP1 modulatory activity. These compounds mapped well onto four of the five features of the pharmacophore. The pharmacophore proposed here was then utilised for the successful retrieval of active molecules with diverse chemotypes from database search. The geometry and features of pharmacophore are expected to be useful for the design of selective MRP1 inhibitors. Figure Alignment of multidrug resistance-associated protein (MRP1) inhibitors with the developed pharmacophore. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Aromaticity and electronic properties of Heterosuperbenzene (Heterohexabenzocoronene)

A global electrophilicity parameter and the aromaticity of some heterocyclic polyaromatic hydrocarbons were evaluated on the basis of DFT calculations. The substitution of carbon atoms by nitrogen atoms dramatically changes the global electrophilicity of the molecules, with the fully substituted molecule being the most electrophilic with a reactivity very close to that of fullerene. Figure Fully substituted heterohexabenzocoronene Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Molecular docking guided 3D-QSAR CoMFA analysis of N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of leukocyte-specific protein tyrosine kinase

Inhibition of leukocyte-specific protein tyrosine kinase (Lck) activity offers one of the approaches for the treatment of T-cell mediated inflammatory disorders including rheumatoid arthritis, transplant rejection and inflammatory bowel disease. To explore the relationship between the structures of the N-4 Pyrimidinyl-1H-indazol-4-amines and their Lck inhibition, 3D-QSAR study using CoMFA analysis have been performed on a dataset of 42 molecules. The bioactive conformation of the template molecule, selected as the most potent molecule 23 from the series was obtained by performing molecular docking at the ATP binding site of Lck, which is then used to build the rest of the molecules in the series. The constructed CoMFA model is robust with of 0.603 and conventional r² of 0.983. The predictive power of the developed model was obtained using a test set of 10 molecules, giving predictive correlation coefficient of 0.921. CoMFA contour analysis was performed to obtain useful information about the structural requirements for the Lck inhibitors which could be utilized in its future design. Figure CoMFA steric contour map. Sterically favored areas (contribution level 80%) are represented by green polyhedra. Sterically disfavored areas (contribution level 20%) are represented by yellow polyhedra. The active molecule 23 shown in capped sticks. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Molecular modeling of the three-dimensional structure of GLP-1R and its interactions with several agonists

Glucagon-like peptide-1 receptor (GLP-1R) is a promising molecular target for developing drugs treating type 2 diabetes. We have predicted the complete three-dimensional structure of GLP-1R and the binding modes of several GLP-1R agonists, including GLP-1, Boc5, and Cpd1, through a combination of homology modeling, molecular docking, and long-time molecular dynamics simulation on a lipid bilayer. Our model can reasonably interpret the results of a number of mutation experiments regarding GLP-1R as well as the successful modification to GLP-1 by Liraglutide. Our model is also validated by a recently revealed crystal structure of the extracellular domain of GLP-1R. An activation mechanism of GLP-1R agonists is proposed based on the principal component analysis and normal mode analysis on our predicted GLP-1R structure. Before the complete structure of GLP-1R is determined through experimental means, our model may serve as a valuable reference for characterizing the interactions between GLP-1R and its agonists. Figure Comparison of our predicted model of rGLP-1R (left) with the recently revealed crystal structure of hGLP-1R (right)     

A theoretical investigation of cytotoxic activity of celastroid triterpenoids

Quantum chemical calculations at the B3LYP/6-31G* level of theory have been carried out on 20 celastroid triterpenoids to obtain a set of molecular electronic properties and to correlate these with cytotoxic activities. The cytotoxic activities of these compounds can be roughly correlated with electronic effects related to nucleophilic addition to C(6) of the compounds: The energies of the frontier molecular orbitals (E _HOMO and E _LUMO), the HOMO-LUMO energy gap, the dipole moment, the charge on C(6), and the electrophilicity on C(6). Figure LUMO of Pristimerin.     

Alpha particle chemistry. On the formation of stable complexes between He2+ and other simple species: implications for atmospheric and interstellar chemistry

The possibility that stable complexes may be formed between alpha particles (He²⁺) and small molecules is investigated using QCISD quantum mechanical calculations. Implications for their presence in the terrestrial atmosphere and/or in interstellar space are discussed. Figure Optimized structure of a stable H₂OHe²⁺ complex     

Two C-terminal ankyrin repeats form the minimal stable unit of the ankyrin repeat protein p18INK4c

Ankyrin repeat proteins (ARPs) appear to be abundant in organisms from all phyla, and play critical regulatory roles, mediating specific interactions with target biomolecules and thus ordering the sequence of events in diverse cellular processes. ARPs possess a non-globular scaffold consisting of repeating motifs named ankyrin (ANK) repeats, which stack on each other. The modular architecture of ARPs provides a new paradigm for understanding protein stability and folding mechanisms. In the present study, the stability of various C-terminal fragments of the ARP p18^INK4c was investigated by all-atomic 450 ns molecular dynamics (MD) simulations in explicit water solvent. Only motifs with at least two ANK repeats made stable systems in the available timescale. All smaller fragments were unstable, readily losing their native fold and α-helical content. Since each non-terminal ANK repeat has two hydrophobic sides, we may hypothesize that at least one hydrophobic side must be fully covered and shielded from the water as a necessary, but not sufficient, condition to maintain ANK repeat stability. Consequently, at least two ANK repeats are required to make a stable ARP. Figure Structure of the p18INK4c protein (PDB entry 1IHB, chain B), which is a member of the cyclin-dependent kinase inhibitor (INK) tumor suppressor family with five ankyrin (ANK) repeat modules. The figure was generated by PyMol Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Modeling the spontaneous initiation of the polymerization of methyl methacrylate

The mechanism of the spontaneous initiation of the polymerization of methyl methacrylate (MMA) was investigated theoretically. The six minimum energy paths (MEP) of the possible reactions were calculated using the density functional theory (DFT) in conjunction with the B3LYP functional and 6-31G* basis set. The Diels-Alder initiation mechanism (path (I) and path (II)) with remarkably high energy barriers is not applicable to MMA. Four favorable paths were found (path (III), path (IV), path (V) and path (VI)), which are supporting the Flory mechanism. Path (V) has the lowest active energy. Therefore this path is considered as the main path for the spontaneous polymerization of MMA. Figure The mechanism of the spontaneous initiation of the polymerization of methyl methacrylate (MMA) was investigated theoretically. The six minimum energy paths (MEP) of the possible reactions were calculated using the density functional theory (DFT) in conjunction with the B3LYP functional and 6-31G* basis set.     

TCNE-aniline charge transfer complex: ab initio and TDDFT investigations in gas phase

The geometric and electronic structure of tetracyanoethylene (TCNE)-aniline (donor-acceptor type) complex has been investigated in gas phase using ab initio and time dependent density functional theory calculations. Both the above calculations predict a composed structure for the complex, in which the interacting site is a C≡N and C=C bond center in the TCNE and, –NH₂ and π-electrons of aniline. The N atom of aniline is oriented toward the TCNE molecule. The charge transfer transition energy, estimated by calculating the ground-to-excited state transition electric dipole moments of the complex, agree well with the reported experimental value in chloroform medium. TCNE-aniline at ground state. TCNE-aniline at excited state     

Optimization of cutting schemes for the evaluation of molecular electrostatic potentials in proteins via Moving-Domain QM/MM

This work presents new developments of the moving-domain QM/MM (MoD-QM/MM) method for modeling protein electrostatic potentials. The underlying goal of the method is to map the electronic density of a specific protein configuration into a point-charge distribution. Important modifications of the general strategy of the MoD-QM/MM method involve new partitioning and fitting schemes and the incorporation of dynamic effects via a single-step free energy perturbation approach (FEP). Selection of moderately sized QM domains partitioned between and C (from C=O), with incorporation of delocalization of electrons over neighboring domains, results in a marked improvement of the calculated molecular electrostatic potential (MEP). More importantly, we show that the evaluation of the electrostatic potential can be carried out on a dynamic framework by evaluating the free energy difference between a non-polarized MEP and a polarized MEP. A simplified form of the potassium ion channel protein Gramicidin-A from Bacillus brevis is used as the model system for the calculation of MEP. Figure Schematic representation of the Moving Domain QM/MM method     

Ab initio analysis of the Cope rearrangement of germacrane sesquiterpenoids

The energetics of the Cope rearrangement of 17 germacrane sesquiterpenoids to their respective elemane forms have been calculated using both density functional theory (B3LYP/6-31G*) and post Hartee-Fock (MP2/6-31G**) ab initio methods. The calculations are in qualitative agreement with experimentally observed Cope rearrangements, but the two methods give slightly different results. MP2 calculations generally show more favorable elemene energies compared to the respective germacrenes (by around 3–4 kcal mol⁻¹) and smaller activation energies (by 2–3 kcal mol⁻¹). Additionally, neither method is accurate enough to consistently reproduce the germacrene/elemene equilibrium. Apparently, the generally small energy differences between the two forms in these sesquiterpenoids cannot be adequately reproduced at these levels of calculation. Figure The Cope rearrangement of the germacrane sesquiterpenoid bacchascandon to the elemane shyobunone     

Docking studies suggest ligand-specific δ-opioid receptor conformations

An automated docking procedure was used to study binding of a series of δ-selective ligands to three models of the δ-opioid receptor. These models are thought to represent the three ligand-specific receptor conformations. Docking results are in agreement with point mutation studies and suggest that different ligands—agonists and antagonists—may bind to the same binding site under different receptor conformations. Docking to different receptor models (conformations) also suggests that by changing to a receptor-specific conformation, the receptor may open or close different binding sites to other ligands. Figure  Ligands 5 (green) and 6 (orange) in bindingpocket BP1 of the R1 δ-opioid receptor model