Understanding the microscopic origin behind heterogeneous properties of water confined in and around Aβ17-42 protofilaments.

Aggregation of amyloid beta (Aβ) peptides in the brain is responsible for one of the most devastating neurodegenerative diseases, namely, Alzheimer's disease. In this study, we have carried out atomistic molecular dynamics simulations to explore the effects of non-uniform structural distortions of Aβ17-42 pre-fibrillar aggregates of different sizes on the microscopic structure and ordering of water molecules confined within their amphiphilic nanocores. The calculations revealed non-uniform peptide-water interactions resulting in simultaneous existence of both highly ordered and disordered water molecules within the spatially heterogeneous confined environment of the protofilament cores. It is found that the high degree of ordering originates from a sizable fraction of doubly coordinated core water molecules, while the randomly oriented ones are those that are coordinated with three neighbors in their first coordination shells. Furthermore, it is quantitatively demonstrated that relative fractions of these two types of water molecules are correlated with the protofilament core topology and the degree of confinement within that. It is proposed that the ordered core waters are likely to stabilize the Aβ protofilaments by screening the residue charges and favoring water-mediated salt bridge formations, while the randomly oriented ones can drive further growth of the protofilaments by being displaced easily during the docking of additional peptides. In that way, both types of core water molecules can play equally important roles in controlling the growth and stability of the Aβ-aggregates.