| 1. |
- Brath, Ulrika, et al.
(författare)
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Paramagnetic ligand tagging to identify protein binding sites
- 2015
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 137:35, s. 11391-11398
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Tidskriftsartikel (refereegranskat)abstract
- Transient biomolecular interactions are the cornerstones of the cellular machinery. The identification of the binding sites for low affinity molecular encounters is essential for the development of high affinity pharmaceuticals from weakly binding leads but is hindered by the lack of robust methodologies for characterization of weakly binding complexes. We introduce a paramagnetic ligand tagging approach that enables localization of low affinity protein–ligand binding clefts by detection and analysis of intermolecular protein NMR pseudocontact shifts, which are invoked by the covalent attachment of a paramagnetic lanthanoid chelating tag to the ligand of interest. The methodology is corroborated by identification of the low millimolar volatile anesthetic interaction site of the calcium sensor protein calmodulin. It presents an efficient route to binding site localization for low affinity complexes and is applicable to rapid screening of protein–ligand systems with varying binding affinity.
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| 2. |
- Carlsson, Anna-Carin, 1976, et al.
(författare)
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Substituent Effects on the [N–I–N]+ Halogen Bond
- 2016
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 138:31, s. 9853-9863
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated the influence of electron density on the three-center [N–I–N]+ halogen bond. A series of [bis(pyridine)iodine]+ and [1,2-bis((pyridine-2-ylethynyl)benzene)iodine]+ BF4– complexes substituted with electron withdrawing and donating functionalities in the para-position of their pyridine nitrogen were synthesized and studied by spectroscopic and computational methods. The systematic change of electron density of the pyridine nitrogens upon alteration of the para-substituent (NO2, CF3, H, F, Me, OMe, NMe2) was confirmed by 15N NMR and by computation of the natural atomic population and the π electron population of the nitrogen atoms. Formation of the [N–I–N]+ halogen bond resulted in >100 ppm 15N NMR coordination shifts. Substituent effects on the 15N NMR chemical shift are governed by the π population rather than the total electron population at the nitrogens. Isotopic perturbation of equilibrium NMR studies along with computation on the DFT level indicate that all studied systems possess static, symmetric [N–I–N]+ halogen bonds, independent of their electron density. This was further confirmed by single crystal X-ray diffraction data of 4-substituted [bis(pyridine)iodine]+ complexes. An increased electron density of the halogen bond acceptor stabilizes the [N···I···N]+ bond, whereas electron deficiency reduces the stability of the complexes, as demonstrated by UV-kinetics and computation. In contrast, the N–I bond length is virtually unaffected by changes of the electron density. The understanding of electronic effects on the [N–X–N]+ halogen bond is expected to provide a useful handle for the modulation of the reactivity of [bis(pyridine)halogen]+-type synthetic reagents.
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| 3. |
- Carlsson, Anna-Carin, 1976, et al.
(författare)
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Symmetric Halogen Bonding is Preferred in Solution
- 2012
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 134, s. 5706-5715
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Tidskriftsartikel (refereegranskat)abstract
- Halogen bonding is a recently rediscovered secondary interaction that shows potential to become a complementary molecular tool to hydrogen bonding in rational drug design and in material sciences. Whereas hydrogen bond symmetry has been the subject of systematic studies for decades, the understanding of the analogous three-center halogen bonds is yet in its infancy. The isotopic perturbation of equilibrium (IPE) technique with 13C NMR detection was applied to regioselectively deuterated pyridine complexes to investigate the symmetry of [N−I−N]+ and [N−Br−N]+ halogen bonding in solution. Preference for a symmetric arrangement was observed for both a freely adjustable and for a conformationally restricted [N−X−N]+ model system, as also confirmed by computation on the DFT level. A closely attached counterion is shown to be compatible with the preferred symmetric arrangement. The experimental observations and computational predictions reveal a high energetic gain upon formation of symmetric, three-center four-electron halogen bonding. Whereas hydrogen bonds are generally asymmetric in solution and symmetric in the crystalline state, the analogous bromine and iodine centered halogen bonds prefer symmetric arrangement in solution.
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| 4. |
- Jimmink, Bono, et al.
(författare)
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Probing Halogen Bonds by Scalar Couplings
- 2021
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 143:28, s. 10695-10699
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Tidskriftsartikel (refereegranskat)abstract
- As halogen bonding is a weak, transient interaction, its description in solution is challenging. We demonstrate that scalar coupling constants (J) are modulated by halogen bonding. The binding-induced magnitude change of one-bond couplings, even up to five bonds from the interaction site, correlates to the interaction strength. We demonstrate this using the NMR data of 42 halogen-bonded complexes in dichloromethane solution and by quantum chemical calculations. Our observation puts scalar couplings into the toolbox of methods for characterization of halogen bond complexes in solution and paves the way for their applicability for other types of weak σ-hole interactions.
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| 5. |
- Karim, Alavi, 1986, et al.
(författare)
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Carbon's Three-Center, Four-Electron Tetrel Bond, Treated Experimentally
- 2018
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 140:50, s. 17571-17579
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Tidskriftsartikel (refereegranskat)abstract
- © 2018 American Chemical Society. Tetrel bonding is the noncovalent interaction of group IV elements with electron donors. It is a weak, directional interaction that resembles hydrogen and halogen bonding yet remains barely explored. Herein, we present an experimental investigation of the carbon-centered, three-center, four-electron tetrel bond, [N-C-N]+, formed by capturing a carbenium ion with a bidentate Lewis base. NMR-spectroscopic, titration-calorimetric, and reaction-kinetic evidence for the existence and structure of this species is reported. The studied interaction is by far the strongest tetrel bond reported so far and is discussed in comparison with the analogous halogen bond. The necessity of the involvement of a bidentate Lewis base in its formation is demonstrated by providing spectroscopic and crystallographic evidence that a monodentate Lewis base induces a reaction rather than stabilizing the tetrel bond complex. A vastly decreased Lewis basicity of the bidentate ligand or reduced Lewis acidity of the carbenium ion weakens - or even prohibits - the formation of the tetrel bond complex, whereas synthetic modifications facilitating attractive orbital overlaps promote it. As the geometry of the complex resembles the SN2 transition state, it provides a model system for the investigation of fundamental reaction mechanisms and chemical bonding theories.
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| 6. |
- Lindblad, Sofia, et al.
(författare)
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Halogen Bond Asymmetry in Solution
- 2018
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 140, s. 13503-13513
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Tidskriftsartikel (refereegranskat)abstract
- © 2018 American Chemical Society. Halogen bonding is the noncovalent interaction of halogen atoms in which they act as electron acceptors. Whereas three-center hydrogen bond complexes, [D···H···D]+ where D is an electron donor, exist in solution as rapidly equilibrating asymmetric species, the analogous halogen bonds, [D···X···D]+, have been observed so far only to adopt static and symmetric geometries. Herein, we investigate whether halogen bond asymmetry, i.e., a [D-X···D]+ bond geometry, in which one of the D-X bonds is shorter and stronger, could be induced by modulation of electronic or steric factors. We have also attempted to convert a static three-center halogen bond complex into a mixture of rapidly exchanging asymmetric isomers, [D···X-D]+ ⇄ [D-X···D]+, corresponding to the preferred form of the analogous hydrogen bonded complexes. Using 15N NMR, IPE NMR, and DFT, we prove that a static, asymmetric geometry, [D-X···D]+, is obtained upon desymmetrization of the electron density of a complex. We demonstrate computationally that conversion into a dynamic mixture of asymmetric geometries, [D···X-D]+ r← [D-X···D]+, is achievable upon increasing the donor-donor distance. However, due to the high energetic gain upon formation of the three-center-four-electron halogen bond, the assessed complex strongly prefers to form a dimer with two static and symmetric three-center halogen bonds over a dynamic and asymmetric halogen bonded form. Our observations indicate a vastly different preference in the secondary bonding of H+ and X+. Understanding the consequences of electronic and steric influences on the strength and geometry of the three-center halogen bond provides useful knowledge on chemical bonding and for the development of improved halonium transfer agents.
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| 7. |
- Perrin, Charles L, et al.
(författare)
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One-bond C-C coupling constants in ethers are not primarily determined by N-sigma delocalization.
- 2005
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 127:17, s. 6168-9
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Tidskriftsartikel (refereegranskat)abstract
- One-bond carbon-carbon coupling constants, 1JCC, were measured for a series of cyclic and acyclic ethers. Surprisingly, the dependence on COCC dihedral angle, tau, parallels cos(tau), rather than the cos(2tau) characteristic of n-sigma* delocalization. These results complement recently calculated 1JCH values in three ethers. The variations in 1J are not primarily determined by delocalization but instead are attributed to a dipolar interaction that affects electron density, perhaps via the hybridization.
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| 8. |
- Perrin,, et al.
(författare)
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Stereochemistry of b-Deuterium Isotope Effects on Amine Basicity
- 2005
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Ingår i: J. Am. Chem. Soc.. - : American Chemical Society (ACS). ; 127:26, s. 9641-7
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Tidskriftsartikel (refereegranskat)abstract
- Secondary â-deuterium isotope effects on amine basicities are measured using a remarkably precise NMR titration method. Deuteration is found to increase the basicity of methylamine, dimethylamine, benzylamine, N,N-dimethylaniline, 2-methyl-2-azanorbornane, and pyrrolizidine. The increase in dimethylamine arises entirely from enthalpy, contrary to a previous report. The method permits a determination of intramolecular isotope effects in 1-benzyl-4-methylpiperidine and 2-benzyl-2-azanorbornane. It is found that deuteration has a larger isotope effect when either antiperiplanar or synperiplanar to a lone pair, but the synperiplanar effect is smaller, as confirmed by computations. The isotope effect is attributed to a lowered zero-point energy of a C-H bond adjacent to an amine nitrogen, arising from delocalization of either a syn or an anti lone pair, and with no detectable angle-independent inductive effect.
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| 9. |
- Peuker, Sebastian, et al.
(författare)
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Efficient Isotope Editing of Proteins for Site-Directed Vibrational Spectroscopy
- 2016
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 138:7, s. 2312-2318
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Tidskriftsartikel (refereegranskat)abstract
- Vibrational spectra contain unique information on protein structure and dynamics. However, this information is often obscured by spectral congestion, and site-selective information is not available. In principle, sites of interest can be spectrally identified by isotope shifts, but site-specific isotope labeling of proteins is today possible only for favorable amino acids or with prohibitively low yields. Here we present an efficient cell-free expression system for the site-specific incorporation of any isotope-labeled amino acid into proteins. We synthesized 1.6 mg of green fluorescent protein with an isotope-labeled tyrosine from 100 mL of cell free reaction extract. We unambiguously identified spectral features of the tyrosine in the fingerprint region of the time-resolved infrared absorption spectra. Kinetic analysis confirmed the existence of an intermediate state between photoexcitation and proton transfer that lives for 3 ps. Our method lifts vibrational spectroscopy of proteins to a higher level of structural specificity.
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| 10. |
- Reiersolmoen, A. C., et al.
(författare)
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Catalytic Activity of trans-Bis(pyridine)gold Complexes
- 2020
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 142:13, s. 6439-6446
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Tidskriftsartikel (refereegranskat)abstract
- Gold catalysis has become one of the fastest growing fields in chemistry, providing new organic transformations and offering excellent chemoselectivities under mild reaction conditions. Methodological developments have been driven by wide applicability in the synthesis of complex structures, whereas the mechanistic understanding of Au(III)-mediated processes remains scanty and have become the Achilles' heel of methodology development. Herein, the systematic investigation of the reactivity of bis(pyridine)-ligated Au(III) complexes is presented, based on NMR spectroscopic, X-ray crystallographic, and DFT data. The electron density of pyridines modulates the catalytic activity of Au(III) complexes in propargyl ester cyclopropanation of styrene. To avoid strain induced by a ligand with a nonoptimal nitrogen-nitrogen distance, bidentate bis(pyridine)-Au(III) complexes convert into dimers. For the first time, bis(pyridine)Au(I) complexes are shown to be catalytically active, with their reactivity being modulated by strain.
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