Connecting Macroscopic Observables and Microscopic Assembly Events in Amyloid Formation Using Coarse Grained Simulations

The pre-fibrillar stages of amyloid formation have been implicated in cellular toxicity, but have proved to be challenging to study directly in experiments and simulations. Rational strategies to suppress the formation of toxic amyloid oligomers require a better understanding of the mechanisms by which they are generated. We report Dynamical Monte Carlo simulations that allow us to study the early stages of amyloid formation. We use a generic, coarse-grained model of an amyloidogenic peptide that has two internal states: the first one representing the soluble random coil structure and the second one the -sheet conformation. We find that this system exhibits a propensity towards fibrillar self-assembly following the formation of a critical nucleus. Our calculations establish connections between the early nucleation events and the kinetic information available in the later stages of the aggregation process that are commonly probed in experiments. We analyze the kinetic behaviour in our simulations within the framework of the theory of classical nucleated polymerisation, and are able to connect the structural events at the early stages in amyloid growth with the resulting macroscopic observables such as the effective nucleus size. Furthermore, the free-energy landscapes that emerge from these simulations allow us to identify pertinent properties of the monomeric state that could be targeted to suppress oligomer formation. Author Summary: A number of normally soluble proteins can form amyloid structures in a process associated with neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Mature amyloid structures consist of large fibrils containing thousands of individual proteins aggregated into linear nanostructures; there is increasing evidence, however, that the toxic species responsible for neurodegeneration are not the mature fibrils themselves but rather lower molecular weight precursors commonly known as amyloid oligomers. Unfortunately, these early oligomers are commonly thermodynamically unstable and of nanometer scale dimensions, factors which make them highly challenging to probe in detail in experiments. We have used computer simulations of a model inspired by Alzheimer's Abeta peptide to investigate the early stages of protein aggregation. The results that we obtain were shown to fit Oosawa's polymerization theory, a finding which allows us to provide a connection between the microscopic molecular parameters and macroscopic growth. One crucial parameter is size of the nucleus, i.e. the basic oligomer existing at origin of the formation of each fiber. We have revealed a path for the formation of this nucleus and validate its size by several methods. Our results provide fundamental information for influencing the early stages of amyloid formation in a rational manner.