Use this URL to cite or link to this record in EThOS:
Title: Diphenylalanine self-assembly- kinetics, thermodynamics and its relevance to amyloidogenesis
Author: Mason, Thomas Oliver
ISNI:       0000 0004 7231 7883
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2018
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Please try the link below.
Access from Institution:
Diphenylalanine (FF) is a dipeptide capable of self-assembly in aqueous solution into needle-like hollow micro- and nanocrystals that possess advantageous properties such as high stiffness and piezoelectricity and have emerged as attractive candidates for functional nanomaterials. In addition, these structures can be made conductive or used as scaffolds for organising functional entities which do not on their own possess a propensity towards self-assembly. At the start of this project, despite wide-ranging interest in the FF assemblies, many important and fundamental aspects of the system remained relatively unexplored. The scope of the present work ranges from nanomaterials science to the relevance of the dipeptide as a model system for the study of aromatic $\pi$-stacking interactions in amyloidogenesis. The basic thermodynamic parameters of FF assembly, the kinetics of that process, and the similarities with, and differences from, the process of fibrillogenesis in polypeptides are explored in detail. The solubility of diphenylalanine in a range of organic solvents and the role of cosolvents in the kinetics of structural assembly were systematically investigated. We find that not only the crystal habit depends on the solvent conditions, but indeed different solvomorphs, possibly differing greatly in mechanical properties, can be obtained from self-assembly in different solvents. The thermodynamics of the dipeptide self-assembly are calculated and placed in the context of earlier work on the free energy of fibril elongation for a range of amyloidogenic polypeptides. It is established that FF aggregation displays the temperature dependence typical of hydrophobic desolvation processes, and that as a model amyloid-forming peptide it displays greater aggregation propensity per amino acid than naturally-occurring polypeptides, due in part to its crystalline as opposed to fibrillar aggregate state. Transition-state measurements are made and the nature of the transition state is elucidated- at the highest-energy point on the aggregation pathway, it is thought that the hydrophobic substituents are still solvent-exposed. The kinetics of self-assembly as a function of solution concentration are quantified through the use of microfluidic techniques, enabling high precision, time-resolved monitoring of the growth process. This work represents the first systematic study of the dependence of the growth rate of diphenylalanine on solution supersaturation. It is found that the aggregation process occurs through established mechanisms of crystal growth. The detailed dependence is shown, and the applicability of the results is demonstrated through the control of the aspect ratio of populations of the assemblies.
Supervisor: Knowles, Tuomas P. J. Sponsor: Newman Foundation ; Elan Pharmaceuticals
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Dipeptides ; Biocrystals ; Crystallisation