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.     

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     

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.     

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.     

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.     

A computational approach to the synthesis of 1,3,5-thiadiazinane-2-thiones in aqueous medium: theoretical evidence for water-promoted heterocyclization

Based on experimental evidence and DFT studies, a probable cyclization route to 1,3,5-thiadiazinanes-2-thiones in aqueous medium is proposed. Experimental facts suggest the formation of a {[hydroxymethyl (substituted) carbamothioyl] sulfanyl}methanol intermediate via reaction of dithiocarbamate (DTC) and formaldehyde. Nucleophilic addition of glycine to this intermediate generates an adduct that undergoes intramolecular heterocyclization via an S_N2 reaction. Computational calculations predict an active role of water in the reaction mechanism that promotes intramolecular cyclization. Figure Energy profile of the proposed reaction mechanism for the synthesis of thiadiazinane-2-thione ring 11 in aqueous medium from a (hydroxymethylcarbamothioyl)sulfanylmethanol intermediate, 9     

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.     

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.     

ONIOM DFT/PM3 calculation on the interaction between STI-571 and abelson tyrosine kinase

The ONIOM2 (B3LYP/6–31G (d, p): PM3) and B3LYP/6–31G (d, p) methods were applied to investigate the interaction between STI-571 and abelson tyrosine kinase binding site. The complex of N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)- phenyl]-benzamide (part of STI-571) and related 16 amino acid residues were found at B3LYP/6–31G (d, p) level to have hydrogen bonds and π....π stacking interaction, their binding energy via HAF optimization was −20.4 kcal mol⁻¹. The results derived from this study agreed well with the reported observation. Figure Optimized structure of STI-571 and Thr315 in abelson tyrosine kinase based on ONIOM2 method     

Optimization of parameters for semiempirical methods V: Modification of NDDO approximations and application to 70 elements

Several modifications that have been made to the NDDO core-core interaction term and to the method of parameter optimization are described. These changes have resulted in a more complete parameter optimization, called PM6, which has, in turn, allowed 70 elements to be parameterized. The average unsigned error (AUE) between calculated and reference heats of formation for 4,492 species was 8.0 kcal mol⁻¹. For the subset of 1,373 compounds involving only the elements H, C, N, O, F, P, S, Cl, and Br, the PM6 AUE was 4.4 kcal mol⁻¹. The equivalent AUE for other methods were: RM1: 5.0, B3LYP 6–31G*: 5.2, PM5: 5.7, PM3: 6.3, HF 6–31G*: 7.4, and AM1: 10.0 kcal mol⁻¹. Several long-standing faults in AM1 and PM3 have been corrected and significant improvements have been made in the prediction of geometries. Figure Calculated structure of the complex ion [Ta₆Cl₁₂]²⁺ (footnote): Reference value in parenthesis Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Evolutionarily evolved discriminators in the 3-TPR domain of the Toc64 family involved in protein translocation at the outer membrane of chloroplasts and mitochondria

Transport of polypeptides across membranes is a general and essential cellular process utilised by molecular machines. At least one component of these complexes contains a domain composed of three tetratricopeptide repeat (3-TPR) motifs. We have focussed on the receptor Toc64 to elucidate the evolved functional specifications of its 3-TPR domain. Toc64 is a component of the Toc core complex and functionally replaces Tom70 at the outer membrane of mitochondria in plants. Its 3-TPR domain recognises the conserved C-terminus of precursor-bound chaperones. We built homology models of the 3-TPR domain of chloroplastic Toc64 from different species and of the mitochondrial isoform from Arabidopsis. Guided by modelling, we identified residues essential for functional discrimination of the differently located isoforms to be located almost exclusively on the convex surface of the 3-TPR domain. The only exception is at568Ser/ps557Met, which is positioned in the ligand-binding groove. The functional implications of the homology models are discussed. Figure Motion contained within the 2nd eigenvector of the Calpha covariance matrix of the 3-TPR domain of atToc64-V indicated by a porcupine plot Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Computational studies of the binding site of α<Subscript>1A</Subscript>-adrenoceptor antagonists

Aimed at achieving a good understanding of the 3-dimensional structures of human α_1A-adrenoceptor (α_1A-AR), we have successfully developed its homology model based on the crystal structure of β₂-AR. Subsequent structural refinements were performed to mimic the receptor’s natural membrane environment by using molecular mechanics (MM) and molecular dynamics (MD) simulations in the GBSW implicit membrane model. Through molecular docking and further simulations, possible binding modes of subtype-selective α_1A-AR antagonists, Silodosin, RWJ-69736 and (+)SNAP-7915, were examined. Results of the modeling and docking studies are qualitatively consistent with available experimental data from mutagenesis studies. The homology model built should be very useful for designing more potent subtype-selective α_1A-AR antagonists and for guiding further mutagenesis studies. Figure The superposition of β₂-AR crystal structure (gold ribbons) and α_1A-AR homology model (blue ribbons)     

Theoretical study on the ground state intramolecular proton transfer (IPT) and solvation effect in two Schiff bases formed by 2-aminopyridine with 2-hydroxy-1- naphthaldehyde and 2-hydroxy salicylaldehyde

The tautomerization mechanism the isolated and monohydrated forms of two Schiff bases 1 and 2, and the effect of solvation on the proton transfer from enol-imine form to the keto-enamine form have been investigated using the B3LYP hybrid density functional method at the 6-31G** basis set level. The barrier heights for H₂O-assisted reactions are significantly lower than that of unassisted tautomerization reaction in the gas phase. Nonspecific solvent effects have also been taken into account by using the continuum model (IPCM) of four different solvent. The tautomerization energies and the potential energy barriers are decreased by increasing solvent polarity. Figure The tautomerization mechanism the isolated and monohydrated forms of two Schiff bases 1 and 2, and the effect of solvation on the proton transfer from enol-imine form to the keto-enamine form have been investigated using the B3LYP hybrid density functional method at the 6-31G** basis set level     

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.     

Electronic analysis of vanadium and iron complexes containing distorted aromatic rings

Aromatic rings can suffer severe distortions upon substituting transition metal centers with certain kinds of organometallic compounds. This property is very interesting because aromaticity can remain despite the deformation. Theoretical calculations at the density functional theory level were carried out on two such structures containing vanadium and iron centres [(C₅H₅-V-H)₂C₆H₆ and (CpFe)₂C₆(CH₃)₆] in order to analyze the nature of the bonds as well as the magnitude of the prevalent aromaticity and how this depends on the electronic characteristics around each metal atom. The analysis of aromaticity was carried out on the basis of known methods, such as HOMA and FLU, with consistent results. The results also show features that suggest a possible catalytic behavior of the species under study. Figure Molecules under study     

The zinc complex catalyzed hydration of alkyl isothiocyanates

Based upon our preceding studies of the hydration of CO₂, COS and CS₂, accelerated by the carbonic anhydrase (CA) using simplified [ZnL₃OH]⁺ complexes as model catalysts, we calculated the hydration mechanisms of both the uncatalyzed and the [ZnL₃OH]⁺-catalyzed reactions (L = NH₃) of isothiocyanates RNCS on the B3LYP/6-311+G(d,p) level of theory. Interestingly, the transition state for the favored metal mediated reaction with the lowest Gibbs free energy is only slightly higher than in the case of CO₂ (depending on the attacking atom (N or S). Calculations under inclusion of solvent corrections show a reduction of the selectivity and a slight decrease of the Gibbs free energy in the rate-determining steps. The most plausible pathway prefers the mechanism via a Lindskog proton-shift transition state leading to the thermodynamically most stable product, the carbamatic-S-acid. Furthermore, powerful electron withdrawing substituents R of the cumulenic substrates influence the selectivity of the reaction to a significant extent. Especially the CF₃-group in trifluoromethylisothiocyanate reverses the selectivity. This investigation demonstrates that reaction principles developed by nature can be translated to develop efficient catalytic methods, in this case presumably for the transformation of a wide variety of heterocumulenes aside from CO₂, COS and CS₂. Figure Competing transition structures for the [ZnL₃OH]⁺-mediated activation of isothiocyanates Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

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.