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The assembly of the amyloid-β peptide (Aβ) into toxic oligomers and fibrils is associated with Alzheimer's disease and dementia. Therefore, disrupting amyloid assembly by direct targeting of the Aβ monomeric form with small molecules or antibodies is a promising therapeutic strategy. However, given the dynamic nature of Aβ, standard computational tools cannot be easily applied for high-throughput structure-based virtual screening in drug discovery projects. In the current study, we propose a computational pipeline—in the framework of the ensemble docking strategy—to identify catechins' binding sites in monomeric Aβ42. It is shown that both hydrophobic aromatic interactions and hydrogen bonding are crucial for the binding of catechins to Aβ42. Additionally, it has been found that all the studied ligands, especially EGCG, can act as potent inhibitors against amyloid aggregation by blocking the central hydrophobic region of Aβ. Our findings are evaluated and confirmed with multi-microsecond MD simulations. Finally, it is suggested that our proposed pipeline, with low computational cost in comparison with MD simulations, is a suitable approach for the virtual screening of ligand libraries against Aβ. [ABSTRACT FROM AUTHOR]

It is shown that the response of molecular properties of diatomics such as the total energy, the bond length, and the vibrational Stark shift to an external homogenous electric field (EF) can be predicted from field-free observable properties such as the equilibrium bond length, the bond dissociation energy, the polarizability and dipole moment functions, and the vibrational frequency. Delley [J. Mol. Struct.: THEOCHEM 434, 229 (1998)] suggested to approximate the potential energy surface under an EF by a Morse function augmented with a EF term proportional to the internuclear separation. In this work, this term is replaced by the expression of the field-induced energy change which yields a field-perturbed Morse potential that tends to a constant asymptotic limit when the EF term itself become proportional to the sum of the polarizabilities of the separated atoms. The model is validated by comparison with direct calculations on nine diatomics, five homo-nuclear (H2, N2, O2, F2, and Cl2) and four hetero-nuclear (HF, HCl, CO, and NO), covering a range and combinations of dipole moments and polarizabilities. Calculations were conducted at the quadratic configuration interaction with single and double excitations (QCISD) and density functional theory (DFT)-B3LYP levels of theory using the 6-311++G(3df,2pd) basis set. All results agree closely at the two levels of theory except for the Stark effect of NO which is not correctly predicted by QCISD calculations as further calculations, including at the coupled cluster with single and double excitation (CCSD) level of theory, demonstrate. [ABSTRACT FROM AUTHOR]

Sulfur tetrafluoride was shown to act as a Lewis acid towards organic nitrogen bases, such as pyridine, 2,6-dimethylpyridine, 4-methylpyridine, and 4-dimethylaminopyridine. The SF4⋅NC5H5, SF4⋅2,6-NC5H3(CH3)2, SF4⋅4-NC5H4(CH3), and SF4⋅4-NC5H4N(CH3)2 adducts can be isolated as solids that are stable below −45 °C. The Lewis acid-base adducts were characterized by low-temperature Raman spectroscopy and the vibrational bands were fully assigned with the aid of density functional theory (DFT) calculations. The electronic structures obtained from the DFT calculations were analyzed by the quantum theory of atoms in molecules (QTAIM). The crystal structures of SF4⋅NC5H5, SF4⋅4-NC5H4(CH3), and SF4⋅4-NC5H4N(CH3)2 revealed weak SN dative bonds with nitrogen coordinating in the equatorial position of SF4. Based on the QTAIM analysis, the non-bonded valence shell charge concentration on sulfur, which represents the lone pair, is only slightly distorted by the weak dative SN bond. No evidence for adducts between quinoline or isoquinoline with SF4 was found by low-temperature Raman spectroscopy. [ABSTRACT FROM AUTHOR]

Quantummechanical methods are used to investigate the chemicalsteps during the bifunctional (glycosylase and β-lyase) activityof bacterial FPG DNA glycosylase, which removes the major oxidationproduct (8-oxoguanine) from DNA as part of the base excision repairprocess. To facilitate investigation of all potential pathways, thesmallest chemically relevant model is implemented, namely a modifiedOG nucleoside-3′-monophosphate and a truncated proline nucleophile.Potential energy surfaces are characterized with SMD-M06-2X/6-311+G(2df,2p)//PCM-B3LYP/6-31G(d) and compared to aprevious study on the analogues human enzyme (hOgg1), which uses alysine nucleophile (Kellie, J. L.; Wetmore, S. D. J. Phys.Chem. B2012, 116, 10786–10797).Our large calculated barriers indicate that FPG must actively catalyzethe three main phases of the overall reaction, namely, deglycosylation,(deoxyribose) ring-opening, and β-elimination, and provide cluesabout how this is achieved through comparison to accurate crystalstructures. The main conclusions about key mechanistic steps holdtrue regardless of the nucleophile, suggesting that most major differencesin the relative activity of FPG and hOgg1 are primarily due to otheractive site residues. Nevertheless, support for possible monofunctional(deglycosylation only) activity is only evident when lysine is thenucleophile. This finding agrees with experimental observations ofmonofunctional activity of hOgg1 and further supports the broadlyaccepted bifunctional activity of FPG. [ABSTRACT FROM AUTHOR]

Thepartitioning of the dipole moment of an isolated molecule or that of a reactingsystem is reviewed and applied to a dynamic reacting system wherebythe system’s dipole moment surface is constructed in parallelto its potential energy surface. The dipole moment surface is thendecomposed into two origin-independent surfaces: (1) an atomic polarization(AP) surface and a charge transfer (CT) surface. The dipole momentsurface as well as its two composing AP and CT surfaces are all furtherbroken down into atomic and/or group contributions with the aid ofthe quantum theory of atoms in molecules (QTAIM). This approach isapplied to the title’s laser-induced chemical reactions [CH4+ •X → CH3•+ HX (X = F, Cl)] previously studied by Bandrauk et al. [J. Chem. Phys.2004, 121, 7764−7775], and which were found to exhibit marked peaks in thedipole moment and in the polarizability tensor component at (or near)the transition state. These peaks afford a means to control the kineticsof these reactions with the proper adjustment of an external laserfield intensity and phase. The entrance channel potentials of thesereactions have recently been probed by photodetachment spectroscopyby Bowman and collaborators [J. Chem. Phys.2011, 134, 191102_1−4]. The understanding of the origin of the peaks in the dipole momentcan provide, eventually, an additional layer of control in the designof reactions tunable by external fields through the proper selectionof the reactants to maximize the field-molecule interaction. [ABSTRACT FROM AUTHOR]

An improved and scalable synthesis of the unsubstituted 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene framework facilitates access to the previously unreported parent dipyrrin HCl salt, as well as 4,4-dichloro-4-bora-3a,4a-diaza-s-indacene. [ABSTRACT FROM AUTHOR]

Stoichiometry of uncoupling proteins (UCPs) and their coexistence as functional monomeric and associated forms in lipid membranes remain intriguing open questions. In this study, tertiary and quaternary structures of UCP2 were analyzed experimentally and through molecular dynamics (MD) simulations. UCP2 was overexpressed in the inner membrane of Escherichia coli , then purified and reconstituted in lipid vesicles. Structure and proton transport function of UCP2 were characterized by circular dichroism (CD) spectroscopy and fluorescence methods. Findings suggest a tetrameric functional form for UCP2. MD simulations conclude that tetrameric UCP2 is a dimer of dimers, is more stable than its monomeric and dimeric forms, is asymmetrical and induces asymmetry in the membrane's lipid structure, and a biphasic on-off switch between the dimeric units is its possible mode of transport. MD simulations also show that the water density inside the UCP2 monomer is asymmetric, with the cytoplasmic side having a higher water density and a wider radius. In contrast, the structurally comparable adenosine 5'-diphosphate (ADP)/adenosine 5'-triphosphate (ATP) carrier (AAC1) did not form tetramers, implying that tetramerization cannot be generalized to all mitochondrial carriers.

Sulfur tetrafluoride was shown to act as a Lewis acid towards organic nitrogen bases, such as pyridine, 2,6-dimethylpyridine, 4-methylpyridine, and 4-dimethylaminopyridine. The SF4 ⋅NC5 H5 , SF4 ⋅2,6-NC5 H3 (CH3 )2 , SF4 ⋅4-NC5 H4 (CH3 ), and SF4 ⋅4-NC5 H4 N(CH3 )2 adducts can be isolated as solids that are stable below -45 °C. The Lewis acid-base adducts were characterized by low-temperature Raman spectroscopy and the vibrational bands were fully assigned with the aid of density functional theory (DFT) calculations. The electronic structures obtained from the DFT calculations were analyzed by the quantum theory of atoms in molecules (QTAIM). The crystal structures of SF4 ⋅NC5 H5 , SF4 ⋅4-NC5 H4 (CH3 ), and SF4 ⋅4-NC5 H4 N(CH3 )2 revealed weak SN dative bonds with nitrogen coordinating in the equatorial position of SF4 . Based on the QTAIM analysis, the non-bonded valence shell charge concentration on sulfur, which represents the lone pair, is only slightly distorted by the weak dative SN bond. No evidence for adducts between quinoline or isoquinoline with SF4 was found by low-temperature Raman spectroscopy., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)