Protein self-assembly leading to fibril formation is an intriguing phenomenon that has been linked to pathological agents in devastating neurodegenerative diseases and has been found to have promising applications in the development of new functional materials. In this dissertation, a combination of ion-mobility mass spectrometry, high level molecular dynamics simulation and microscopy imaging has been employed to investigate the distributions of early oligomers, their conformational transitions in the presence of small-molecule modulators and the structures of toxic and non-toxic oligomers. A variety of biomolecule models was examined to elucidate the driving forces behind amyloid and non-amyloid self-assemblies, and to provide a new approach to aggregation propensity prediction.