Dissertation: “Shape Matters: Characterization of Weak Interactions and Macrocycles by Conformational Analysis”

Stefan Peintner defends his doctoral thesis with the title “Shape Matters: Characterization of Weak Interactions and Macrocycles by Conformational Analysis”, in the subject of Chemistry, with a specialisation in Organic Chemistry.

Opponent: Prof. Oliver Zerbe, University of Zürich, Switzerland

Supervisors: Prof. Máté Erdélyi and Prof. Jan Kihlberg, Department of Chemistry - BMC, Uppsala University

When studying conformational ensembles, it is most challenging to identify and characterize rapidly interconverting individual conformers. A precise description of the structural dynamics, however, rewards viable knowledge on conformation stabilizing forces as well as on the impact of external influences on the conformer composition. This thesis focusses on the solution NMR spectroscopic conformational analysis of flexible molecules with the aim to unveil the impact, strength and geometry of a single weak non-covalent interaction, a halogen bond. In addition, I investigated the impact of the solvent polarity on the conformational distribution of macrocyclic drugs.

Weak interactions are difficult to characterize in solution with current techniques. Therefore, I designed a peptidic β-hairpin model system that serves as platform to probe a single weak halogen bond in solution. The presented strategy benefits from the cooperativity of non-covalent forces, from preorganization, and from the entropic advantage of studying an interaction in an intramolecular setting. A weak C−I···O halogen bond was characterized thermodynamically and geometrically using NMR-based variable temperature, NOE, scalar coupling and RDC analyses. Time-averaged NMR parameters were deconvoluted with NAMFIS and by Singular Value Decomposition as implemented into MSpin. Characterization of such a weak interaction (ΔΔG° < 0.9 kJ/mol) in dilute solution is remarkable.

Making use of NMR-based ensemble analysis, I further studied the impact of solvent polarity on the conformational distribution of macrocyclic drugs that do not obey Lipinski’s Rule-of-5, yet experience good membrane permeability. I demonstrate experimentally that this class of compounds behaves as molecular chameleons by adjusting their conformation to shield or expose polar functionalities as an adaptation to the surrounding environment. Solution ensembles in D2O and CDCl3 mimicking the plasma/cytosol and cell membrane, respectively, were determined and thus revealed that the flexibility of studied macrocycles facilitates a major difference in size and polarity between different environments. 

Overall, this thesis demonstrates the capabilities and precision of solution NMR spectroscopic conformation analysis techniques, and two possible applications of their use for solving scientific challenges of high relevance to medicinal and organic chemistry.

Link to the thesis in full text in DiVA.