| 1. |
- Lidskog, Anna, et al.
(author)
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Experimental and Computational Models for Side Chain Discrimination in Peptide–Protein Interactions
- 2021
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In: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 27:42, s. 10883-10897
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Journal article (peer-reviewed)abstract
- A bis(18-crown-6) Tröger's base receptor and 4-substituted hepta-1,7-diyl bisammonium salt ligands have been used as a model system to study the interactions between non-polar side chains of peptides and an aromatic cavity of a protein. NMR titrations and NOESY/ROESY NMR spectroscopy were used to analyze the discrimination of the ligands by the receptor based on the substituent of the ligand, both quantitatively (free binding energies) and qualitatively (conformations). The analysis showed that an all-anti conformation of the heptane chain was preferred for most of the ligands, both free and when bound to the receptor, and that for all of the receptor-ligand complexes, the substituent was located inside or partly inside of the aromatic cavity of the receptor. We estimated the free binding energy of a methyl- and a phenyl group to an aromatic cavity, via CH-π, and combined aromatic CH-π and π-π interactions to be −1.7 and −3.3 kJ mol−1, respectively. The experimental results were used to assess the accuracy of different computational methods, including molecular mechanics (MM) and density functional theory (DFT) methods, showing that MM was superior.
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| 2. |
- Aspelin, Vidar, et al.
(author)
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Counterintuitive Electrostatics upon Metal Ion Coordination to a Receptor with Two Homotopic Binding Sites
- 2022
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In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 144:7, s. 2921-2932
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Journal article (peer-reviewed)abstract
- The consecutive binding of two potassium ions to a bis(18-crown-6) analogue of Tröger’s base (BCETB) in water was studied by isothermal titration calorimetry using four different salts, KCl, KI, KSCN, and K2SO4. A counterintuitive result was observed: the enthalpy change associated with the binding of the second ion is more negative than that of the first (ΔH°bind,2 < ΔH°bind,1). This remarkable finding is supported by continuum electrostatic theory as well as by atomic scale replica exchange molecular dynamics simulations, where the latter robustly reproduces experimental trends for all simulated salts, KCl, KI, and KSCN, using multiple force fields. While an enthalpic K+–K+attraction in water poses a small, but fundamentally important, contribution to the overall interaction, the probability of the collapsed conformation (COL) of BCETB, where both crown ether moieties (CEs) of BCETB are bent in toward the cavity, was found to increase successively upon binding of the first and second potassium ions. The promotion of the COL conformation reveals favorable intrinsic interactions between the potassium coordinated CEs, which further contribute to the observation that ΔH°bind,2 < ΔH°bind,1. While the observed trend is independent of the counterion, the origin of the significantly larger magnitude of the difference ΔH°bind,2 - ΔH°bind,1 observed experimentally for KSCN was studied in light of the weaker hydration of the thiocyanate anion, resulting in an enrichment of thiocyanate ions close to BCETB compared to the other studied counterions.
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| 3. |
- Li, Yutang, et al.
(author)
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Enantiotopic Discrimination by Coordination-Desymmetrized meso-Ligands
- 2020
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In: ChemCatChem. - : Wiley. - 1867-3880 .- 1867-3899. ; 12:6, s. 1575-1579
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Journal article (peer-reviewed)abstract
- The first examples of enantiopure catalysts that are chiral merely due to coordination of different metal ions at enantiotopic positions of an achiral meso-ligand are reported. These catalysts exhibit a pseudo-Cs symmetry and are able to catalyze reactions demanding simultaneous involvement of two catalytic sites. The latter was demonstrated by application in the asymmetric ring-opening of meso-epoxides.
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| 4. |
- Lidskog, Anna, et al.
(author)
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Asymmetric ring-opening of epoxides catalyzed by metal–salen complexes
- 2020
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In: Catalysts. - : MDPI AG. - 2073-4344. ; 10:6
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Journal article (peer-reviewed)abstract
- The asymmetric ring-opening of epoxides is an important reaction in organic synthesis, since it allows for the enantioselective installation of two vicinal functional groups with specific stereochemistry within one step from a highly available starting material. An effective class of catalysts for the asymmetric ring-opening of epoxides is metal–salen complexes. This review summarizes the development of metal–salen catalyzed enantioselective desymmetrization of meso-epoxides and kinetic resolution of epoxides with various nucleophiles, including the design and application of both homogeneous- and heterogeneous epoxide-opening catalysts as well as multi-metallic covalent and supramolecular catalytic systems.
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| 5. |
- Lidskog, Anna
(author)
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Bicyclo[3.3.1]nonanes as Scaffolds in Supramolecular Chemistry : From Host-Guest Systems to Hydrogen-Bonded Aggregates
- 2023
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Doctoral thesis (other academic/artistic)abstract
- This thesis describes the use of bicyclo[3.3.1]nonane and its heteroanalogue 1,5- diazabicyclo[3.3.1]nonane as scaffolds in different supramolecular systems. The thesis is divided into two parts, with the first part (chapter 2–4) focusing on the development and applications of a synthetic receptor based on a Tröger’s base motif fused with 18-crown-6 moieties. In chapter 3, NMR titration methodology was used to determine relative association constants and binding energies of the binding between the receptor and differently substituted bisammonium ligands. A small but evident discrimination based solely on the substituent was found, with phenyl- and methyl-substituted ligands forming stronger receptor-ligand complexes than ligands with no or larger substituents. By combining the estimated relative binding energies with results from conformational analyses of the receptor-ligand complexes, the free binding energies between a methyl or a phenyl group and an aromatic cavity were estimated to -0.40 and -0.80 kcal/mol, respectively, which is comparable to previously reported values for similar CH-π and π-π interactions.In chapter 4, the consecutive binding of potassium ions to the same ditopic receptor in water is studied. ITC experiments revealed a counterintuitive result: that the binding of the second potassium ion is enthalpically favored compared to the binding of the first. A combination of experiments and simulations were employed to investigate how different factors influence the thermodynamics of the binding process, resulting in the finding that both the counterion and intrinsic favorable interactions between the two potassium-bound crown-ethers contribute to the observed thermodynamic trends. Although further investigations are needed to fully elucidate the different contributions, the herein presented study offers valuable insights into factors affecting receptor/ligand interactions in water.The second part of the thesis (chapter 5–6) describes hydrogen-bonding monomers capable of self- assembling into cyclic and tubular aggregates. With the aim of developing amphiphilic monomers, polyethylene glycol (PEG) chains were introduced to the bicyclic backbone of the monomers. The synthesis and self-assembly of two new PEGylated monomers is described and compared to previously reported alkylated analogues. Both new monomers were capable of forming hydrogen-bonded cyclic aggregates. The effect of the PEG chains on the aggregate stability was found to depend on the hydrogen bond strength. One of the monomers exhibited the desired amphiphilicity and could be extracted from an aqueos solution into a chloroform solution, where self-assembly into cyclic tetramers occurred.
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