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Application of Computational Methods to the Structural and Functional Properties of Flexible Chiral Molecules

In this thesis we used state-of-the-art theoretical methods to investigate two cornerstones of modern chemistry, namely molecular flexibility and chirality, and the interplay between the two. In this respect, we tackled two important scenarios, investigating the behavior of flexible and chiral moieties both in solution and at the interfaces of inorganic surfaces. In the first scenario we investigated the phenomenon of CD spectroscopy, which represents a powerful tool for structural characterization of optically active chiral molecules. Because CD spectrum arises as an ensemble average, in order to properly understand and assign experimental spectral features of flexible molecular species, a theoretical framework becomes necessary. We thus developed a methodology which combines advanced classical molecular dynamics simulations, with which one generates the conformational phase space of a molecule, statistical tools, used to characterize the phase space and extract conformations representing the molecular ensemble, and quantum calculations, via which one obtains the CD spectra. Using our methodology we were able to successfully determine the absolute configuration of small organic compounds. Moreover, and in spite of inherent complexity, we were able to obtain satisfactorily agreement between theory and experiment in the case of flexible peptides, thereby establishing the bridge between the molecular structure and spectra of highly flexible species for the first time. In the second scenario we focused on the behavior of flexible chiral organic molecules at the water – biomineral interface, in an attempt to uncover the roles of flexibility and chirality in biomineralization and biomineralization-inspired drug design. We focused on the calcite – peptide composite systems, representing the most promising bioinorganic systems for pharmaceutical purposes. We thus decided to investigate the interactions of calcite with two highly active peptides/epimers, which are experimentally found to strongly interact with the biomineral. The chosen biomolecule – biomineral composites represent a prototypical drug delivery systems, where the N-termini of the chosen peptides plays the role of a drug, while their remaining parts perform the role of a binder/linker via which they attach to calcite carrier. We characterized these composite systems in depth by employing advanced classical molecular dynamics simulations with enhanced sampling. On one hand, this approach allowed us to analyze the conformational behavior of the adsorbed peptides in detail, while, on the other hand, it permitted us to investigate the underlying thermodynamics of the process by calculating free energy profiles of adsorption. Taken together, our findings enabled us to shed light on the role of flexibility and chirality on both biomineralization and biomineralization- inspired drug design.

chirality ; circular dichroism ; computational methods ; flexiblity ; molecular dynamics simulations

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