Exploring Heterogeneous Dynamical Environment around an Ensemble of Aβ₄₂ Peptide Monomer Conformations

Exploring the conformational properties of amyloid β (Aβ) peptides and the role of solvent (water) in guiding the dynamical environment at their interfaces is crucial for microscopic understanding of Aβ misfolding, which is involved in causing the most common neurodegenerative disorder, i.e., Alzheimer's disease. While numerous studies in the past have emphasized examining the conformational states of Aβ peptides, the role of water has not received much attention. Here, we have performed all-atom molecular dynamics simulations of several full-length Aβ₄₂ peptide monomers with different initial configurations. Our efforts are directed toward probing the origin of the heterogeneous dynamics of water around various segments of the Aβ peptide, identified as the two terminal segments (N-term and C-term) and the two hydrophobic segments (hp1 and hp2), along with the central turn region interconnecting hp1 and hp2. Our results revealed that water hydrating hp1, hp2, and turn (nonterminal segments) and C-term segments exhibit nonuniformly restricted translational as well as rotational motions. The degree of such restriction has been found to be correlated with the hydrogen bond relaxation time scales at the interface. Importantly, it is revealed that the water molecules around hp1 and, to some extent, around hp2, form relatively rigid hydration layers, compared to that around the other segments. Such rigid hydration layers arise due to relatively more solid-like caging motions resulting in relatively lesser hydration entropy. As hp1 and hp2 have been demonstrated to play a central role in Aβ aggregation, we believe that distinct water dynamics in the vicinity of these two segments, as outlined in this study, can provide vital information in understanding the early stages of the onset of the aggregation process of such peptides at higher concentration that can further aid toward advances in AD therapeutics.