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Solution ensemble analysis of macrocycles
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. (Erdelyi group)
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. (Erdelyi group)ORCID iD: 0000-0003-3798-3322
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry. (Erdelyi group)ORCID iD: 0000-0003-0359-5970
2018 (English)Conference paper, Oral presentation with published abstract (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.

Place, publisher, year, edition, pages
2018.
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-371864OAI: oai:DiVA.org:uu-371864DiVA, id: diva2:1274767
Conference
SMASH – Small Molecule NMR Conference, Philadelphia, Pennsylvania, USA, 16-19 september 2018
Available from: 2019-01-03 Created: 2019-01-03 Last updated: 2019-01-07

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Danelius, EmmaAndersson, HannaErdélyi, Máté

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