Insights into the protein interactions with graphitic nanomaterials using computational modelling techniques

In this thesis computational modelling techniques were employed to investigate the behaviour of an amyloidogenic protein in the presence of dimensionally different carbonaceous nanomaterials. Experimental studies have demonstrated that nanoparticles can affect the rate of protein self-assembly, possibly interfering with the development of protein misfolding diseases such as Alzheimer’s, Parkinson’s and prion disease caused by aggregation and fibril formation of amyloid-prone proteins. The computational techniques used in this thesis include large-scale density functional theory calculations and classical molecular dynamics simulations and their derivative methods such as umbrella sampling and replica exchange methods. The behaviour, in solution and various fibril inhibiting and fibril favouring environments, of the amyloidogenic protein apolipoprotein C-II (ApoC-II) and its peptides derivatives are discussed in detail.<br><br> Additionally the graphitic nanomaterials (C60, single walled carbon nanotube and graphene) used throughout this thesis are also described. Initially the effect of the different carbon nanomaterials on the structure, dynamics and binding of the monomeric peptide apoC-II(60-70), all of which can influence its fibril formation capacity, were studied and compared to results obtained from previously characterised peptide behaviour in solution. A combination of computational methods, including large-scale electronic structure calculations and classical all-atom molecular dynamics was utilised. Understanding the effect nanomaterials may have on the early stages of fibril formation and in particular the small oligomeric species that drive the initial fibrillation behaviour is important in identifying how they can either inhibit or promote fibril growth. The adsorption and desorption mechanism of two preformed oligomeric composits of apoC-II(60-70) peptide (dimer and tetramer) were investigated. The adsorption mechanism of the apoC-II(60-70) dimer and tetramer to each nanomaterial was investigated and the results were used to determine if there existed a favourable adsorption mechanism that could impact on the fibrillation ability of the oligomeric peptides. The advanced sampling method known as replica exchange with solute tempering (REST) was applied to investigate the stability and interactions of the apoC-II(60-70) dimer and tetramer while adsorbed to the carbonaceous nanomaterials.<br><br> The results were used to rationalise how nanomaterial curvature, fibril seed size and peptide - nanomaterial binding energy impact the oligomers stability and thus fibrillation ability. The aggregate dynamics and structure of the full length preformed apoC-II tetramer in the presence the different carbonaceous nanomaterials was also explored. The conformational stability and structural dynamics of the apoC-II tetramer while adsorbed to each surface was determined. The results were compared to those obtained throughout the thesis of the peptide derivative apoC-II(60-70) and its oligomers in order to extrapolate the potential effect that these nanomaterials may have on influencing the fibril stability of the full length apoC-II tetramer. To conclude a summary of the overall findings of the thesis and how they may impact the wider research community is presented. Additionally, possible future research into the effect that other graphitic nanomaterials, including graphene-oxide, may have on fibrillation. Another amyloidogenic peptide, amylin, is also discussed as a future target for combating type II diabetes with nano therapeutics.