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  • 1.
    Danelius, Emma
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Solution ensemble analysis of macrocycles2018Conference paper (Refereed)
    Abstract [en]

    Macrocycles are key drug leads for protein targets with large, flat and featureless binding sites, including protein-protein interfaces.  Due to their conformational flexibility macrocycles typically exist as a mixture of interconverting geometries in solution, and hence cannot be represented by a single, averaged conformation.  This flexibility is a result of continuously forming and breaking a number of weak intramolecular interactions.  The yielded conformations in solution vastly impact the bioactivity, solubility and membrane permeability of the macrocycles.  Therefore, describing their conformational ensembles, as well as the impact of conformation stabilizing weak interactions, is of fundamental importance, and the knowledge gained is directly applicable to medicinal chemistry.

    In order to describe macrocycle structure and dynamics, time-averaged solution spectroscopic data has to be deconvoluted into the present conformations along with their respective probability.  We have studied the solution ensembles of a series of macrocycles using the NAMFIS (NMR analysis of molecular flexibility in solution) algorithm.  This combined computational and spectroscopic ensembles analysis deconvolutes time averaged NMR data by identifying the real conformations and assigning them with their molar fractions.  Theoretical ensembles were predicted using Monte Carlo conformational searches with molecular mechanics minimization.  The generated ensembles, typically containing 40-150 conformers, were then used together with experimental NOE-based distances and J-coupling-based dihedral angles to identify the molar fractions of the conformations present in solution.

    We applied this technique to gain understanding of weak chemical interactions in a biologically relevant environment, by analyzing macrocyclic β-hairpin peptides.  The stabilizing effect provided by an interstrand weak interaction, as compared to a reference peptide lacking this interaction, was quantified through ensemble analysis.  We have shown that a single interstrand hydrogen [1,2,3] or halogen bond (Figure 1) [4], can significantly influence the folding, and increase the population of the folded conformation by up to 40%.  The NMR results were corroborated by CD-spectroscopy and MD-calculations.

  • 2.
    Danelius, Emma
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Andersson, Hanna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Jarvoll, Patrik
    Lood, Kajsa
    Gräfenstein, Jürgen
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Halogen bond promoted peptide folding2018Conference paper (Refereed)
    Abstract [en]

    We have developed a β-hairpin peptide model system that permits quantitative evaluation of weak interactions in a biologically relevant environment. The influence of a single weak force was measured by detection of the extent to which it modulates peptide folding. Initially we have optimized a β-hairpin model system, using the simpler to synthesize hydrogen bonding analogues of our target system encompassing halogen bond donor and acceptor sites [1,2,3]. Using a combined computational and NMR spectroscopic ensemble analysis, we have quantified the stabilizing effect of a single secondary interaction on the folded β-hairpin conformation. We have demonstrated that a chlorine centered halogen bond, formed between two amino acid side chains in an interstrand manner (Figure 1), provides a conformational stabilization comparable to the analogous hydrogen bond [4]. The negative control, i.e. the peptide containing a noninteracting aliphatic side chain, was ~30% less folded than the hydrogen and halogen bonding analogues, revealing the high impact of the interstrand interaction on folding. The experimental results are corroborated by computation on the DFT level. This is the first report of quantification of a conformation-stabilizing chlorine centered halogen bond in a peptide system.  

  • 3.
    Peintner, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Danelius, Emma
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Poongavanam, Vasanthanathan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdelyi, Mate
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. The Swedish NMR Centre.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    The Solvent Polarity Dependence of Macrocycles’ Conformations2018Conference paper (Refereed)
  • 4.
    Wieske, Hermina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Danelius, Emma
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Swedish NMR Centre.
    Conformational Analysis of Rifampicin in Solution2018Conference paper (Other academic)
    Abstract [en]

    Rifampicin is a macrocyclic drug used to treat bacterial infections.1 With a mass of 823 Da, rifampicin violates the Lipinki’s rule of five (Ro5),2 and therefore would be expected to have poor membrane permeability, and hence to not be applicable as an oral therapeutic agent. Despite this fact, rifampicin has proven to reach its target in a biological system and thus is able to pass multiple cell membranes without major problems. We hypothesize that the permeability of rifampicin may be explained by its molecular flexibility. We have therefore determined the conformational ensembles of rifampicin in aqueous and in chloroform solutions using the NMR Analysis of Molecular Flexibility in Solution (NAMFIS) approach.3 Comparing the ensembles present in environments possessing different polarities, we hypothesized that simultaneous aqueous solubility and membrane permeability of rifampicin may be explained by its ability to adjust its conformation to the molecular environment. In this presentation the ensemble analysis of rifampicin in polar and non-polar media will be disclosed, and the results will be discussed in relation to the above hypothesis on its permeability. We propose that this macrocycle folds into a conformation with its hydrophilic groups being better shielded from the hydrophobic membrane when it crosses a membrane, whereas it makes its polar functions solvent accessible in a polar environment (Fig. 1).

  • 5.
    Wieske, Hermina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Danelius, Emma
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. Swedish NMR Centre.
    Conformational Analysis of Rifampicin in Solution.2018Conference paper (Other academic)
    Abstract [en]

    Rifampicin is a macrocyclic drug used to treat bacterial infections.1 With a mass of 823 Da, rifampicin violates the Lipinki’s rule of five (Ro5),2 and therefore would be expected to have poor membrane permeability, and hence to not be applicable as an oral therapeutic agent. Despite this fact, rifampicin has proven to reach its target in a biological system and thus is able to pass multiple cell membranes without major problems. We hypothesize that the permeability of rifampicin may be explained by its molecular flexibility. We have therefore determined the conformational ensembles of rifampicin in aqueous and in chloroform solutions using the NMR Analysis of Molecular Flexibility in Solution (NAMFIS) approach.3 Comparing the ensembles present in environments possessing different polarities, we hypothesized that simultaneous aqueous solubility and membrane permeability of rifampicin may be explained by its ability to adjust its conformation to the molecular environment. In this presentation the ensemble analysis of rifampicin in polar and non-polar media will be disclosed, and the results will be discussed in relation to the above hypothesis on its permeability. We propose that this macrocycle folds into a conformation with its hydrophilic groups being better shielded from the hydrophobic membrane when it crosses a membrane, whereas it makes its polar functions solvent accessible in a polar environment (Fig. 1).

  • 6.
    Wieske, Hermina
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Danelius, Emma
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Peintner, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Erdélyi, Máté
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Conformational Analysis of Rifampicin in Solution2018Conference paper (Other academic)
    Abstract [en]

    Rifampicin is a macrocyclic drug used to treat bacterial infections.1 With a mass of 823 Da, rifampicin violates the Lipinki’s rule of five (Ro5),2 and therefore would be expected to have poor membrane permeability, and hence to not be applicable as an oral therapeutic agent. Despite this fact, rifampicin has proven to reach its target in a biological system and thus is able to pass multiple cell membranes without major problems. We hypothesize that the permeability of rifampicin may be explained by its molecular flexibility. We have therefore determined the conformational ensembles of rifampicin in aqueous and in chloroform solutions using the NMR Analysis of Molecular Flexibility in Solution (NAMFIS) approach.3 Comparing the ensembles present in environments possessing different polarities, we hypothesized that simultaneous aqueous solubility and membrane permeability of rifampicin may be explained by its ability to adjust its conformation to the molecular environment. In this presentation the ensemble analysis of rifampicin in polar and non-polar media will be disclosed, and the results will be discussed in relation to the above hypothesis on its permeability. We propose that this macrocycle folds into a conformation with its hydrophilic groups being better shielded from the hydrophobic membrane when it crosses a membrane, whereas it makes its polar functions solvent accessible in a polar environment (Fig. 1).

1 - 6 of 6
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