Solvent effects on hydrogen bonding

Determining the strength of H-bonds in solution can be challenging due to competing solvent interactions, especially in biologically relevant polar solvents such as water. In this thesis, various molecular balance designs are used to quantify the strength of H-bonds in solution. Chapter 1 presents a literature review on optimising H-bond interactions, with a focus on experimental systems previously used to quantify the strength of H-bonds in different solvents. Chapter 2 investigates the effectiveness of implicit solvation models for predicting the thermodynamic behaviour of different solvents using a simple series of molecular balances. Computationally determined equilibrium energies are compared with experimental values. Generally, the implicit solvation models are found to have good correlations in non-polar solvents, but poorer results are observed when moving onto more polar solvents. Chapter 3 provides an experimental study of organic and aqueous solvent effects on intramolecular H-bonding between amide and anilines. Several series of compounds are investigated, where both H-bond geometry and conformational flexibility are varied. Thermodynamic information is derived from the balances and the experimental data examined further by plotting against computational results and fitting with a semi-empirical solvation model. Chapter 4 presents a study on solvent effects on H-bond cooperativity. A phenol, catechol and pyrogallol molecular balance series are synthesised and experimental energies are derived. Three different types of behaviour are observed depending on the acceptor ability of the solvent

Comparison of Implicit and Explicit Solvation Models for <i>Iota</i>-Cyclodextrin Conformation Analysis from Replica Exchange Molecular Dynamics

Large ring cyclodextrins have become increasingly important for drug delivery applications. In this work, we have performed replica-exchange molecular dynamics simulations using both implicit and explicit water solvation models to study the conformational diversity of <i>iota</i>-cyclodextrin containing 14 α-1,4 glycosidic linked d-glucopyranose units (CD14). The new quantifiable calculation methods are proposed to analyze the openness, bending, and twisted conformation of CD14 in terms of circularity, biplanar angle, and one-directional conformation (ODC). CD14 in GB implicit water model (Igb5) was found mostly in an opened conformation with average circularity of 0.39 ± 0.16 and a slight bend with average biplanar angle of 145.5 ± 16.0°. In contrast, CD14 in TIP3P explicit water solvation is significantly twisted with average circularity of 0.16 ± 0.10, while 29.1% are ODCs. In addition, classification of CD14 conformations using a Gaussian mixture model (GMM) shows that 85.0% of all CD14 in implicit water at 300 K correspond to the elliptical conformation, in contrast to 82.3% in twisted form in explicit water. GMM clustering also reveals minority conformations of CD14 such as the 8-shape, boat-form, and twisted conformations. This work provides fundamental insights into CD14 conformation, influence of solvation models, and also proposes new quantifiable analysis techniques for molecular conformation studies in the future