Kinetic and thermodynamic stability comparison for the fibrillar form of small amyloid-β(1-42) oligomers using scaled molecular dynamics.

Amyloid-β (Aβ) oligomers act as intermediates for several neurodegenerative disease-relevant fibril formations. However, gaining insight into the oligomer to fibril conversion process remains a challenge due to the transient nature of small Aβ. In this study, we probe the kinetic and thermodynamic stabilities of small Aβ(1-42) oligomers in fibrillar conformations to understand from what size these aggregates start forming stable fibrils. With no definite structures available for small Aβ42 aggregates, we have started with oligomers extracted from mature fibrils having four, five, six and nine chains stacked together, and have performed order-to-disorder transition on these systems. Using scaled molecular dynamics (sMD) simulation, the timescale for breaking the native contacts of fibrils has been compared. The results indicate that the kinetic stability of oligomers increases with size, especially at the C-terminus end beyond five-chain oligomers. The free energy of breaking the contacts at the β-sheet regions in the structures has been obtained on an unscaled potential from a free energy extrapolation (FEE) approach. The values show that although stable minima are obtained for larger oligomers due to the enhanced stability of the C-terminus ends, fully stable fibril formation may require aggregates larger than the ones considered in our study. Additionally, dissimilar kinetics for the unbinding of terminal chains across all the oligomers has been observed. The interaction energy values calculated from unscaled MD simulations reveal the crucial role of water in our observations. Our work provides the application of an easy-to-deploy method that sheds light on interactions which could be significant in the early stages of Aβ42 fibril formation.