Non-Covalent Interactions in Water Using Synthetic and Biological Receptors

This thesis deals with two different topics, and they will be introduced and discussed separately. The first part of this thesis discusses the factors that govern the nature of aromatic interactions in water. The rational design and interpretation of the supramolecular behaviour of aromatic interactions in aqueous solution represents a major challenge. First, aromatic interaction energies are strongly affected by the geometry of the interaction. Second, molecular recognition in water involves contributions due to polar functional group interactions, partial desolvation of polar and non-polar surfaces and changes in conformational flexibility. Here, conformationally well-defined supramolecular complexes formed between four different calix[4]pyrrole receptors and thirty different pyridine N-oxide guests provide a platform for disentangling the factors that govern aromatic interactions in water and in chloroform. The three-dimensional structures of the complexes are fixed by four H-bonding interactions between the pyrrole donors at the bottom of the receptor and the N-oxide acceptor on the guest, locking the geometrical arrangement of interacting functional groups in the binding pocket at the other end of the receptor, so that an aromatic ring on the guest makes two edge-to-face and two stacking interactions with the four aromatic side-walls of the receptor. The thermodynamic contribution of these aromatic interactions to the overall stability of the complex has been quantified by chemical double mutant cycles using isothermal titration calorimetry and ¹H NMR competition experiments. In chloroform, the free energy measurements of the aromatic interactions show that electron-withdrawing substituents increase the strength of the interactions by a factor of up to 20, highlighting the role of electrostatics in stabilising both the edge-to-face and stacking interactions. The effect of introducing a heteroatom depends on where it sits with respect to the aromatic side-walls of the cavity. In water, aromatic interactions are all significantly more favourable than in chloroform, and the free energy contributions measured in water have been rationalised by comparison with the magnitude of the corresponding measurements in chloroform. The enhanced interaction energies observed in water are due to entropic contributions associated with the desolvation of hydrophobic surfaces on the substituents. There are flexible alkyl chains that line the open end of the binding site and assist the desolvation of the non-polar π-surfaces of the guests, but at the same time allow water to interact with polar H-bond acceptor sites. Moreover, water can access cracks in the walls of receptor binding site without significantly affecting the geometry of the aromatic interactions. The results highlight the complexity of the solvation processes that govern molecular recognition in water. The second part of this thesis discusses attempts to use protein-templated dynamic combinatorial chemistry to speed up the structural optimisation of multivalent molecular probes that bind amyloid fibrillar aggregates. Building blocks consisting of amyloid-binding probes and linkers have been synthesised and attempts at equilibrating a dynamic library of exchanging building blocks between monovalent and divalent constructs under suitable conditions for templating have been made. However, the poor solubility of the library members prohibited the continuation of the study.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Tobajas Curiel, Gloria

Advisor dc:contributor.advisor

• Hunter, Christopher

• physical organic chemistry
• supramolecular chemistry

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/410ddcc6-8307-451d-a0c2-8f96390fb9c5/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.105856

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/364042