Differences in Dynamics and Stability of the Wild Type Beta-Amyloid Aβ1-40, and ΔE22-Aβ1-39 (Japanese) Mutant Protofibril Structures, a Molecular Dynamics Study

Abstract

Alzheimer's disease has been identified as a neurodegenerative disorder associated with protein misfolding due to the aggregation of monomeric beta-amyloid proteins (Aβ) to form fibrillar plaques. Experimental attempts to chemically analyze the structure of Aβ protofibrils and elucidate the mechanism of fibril formation have yet to reveal much about the molecular etiology of AD, due to the low solubility and non-crystalline nature of Aβ. It has been shown experimentally that the ΔE22-Aβ1-39 (Japanese) mutation of β-amyloid leads to production of typical Aβ fibrils essentially instantaneously, much faster than the fibril formation in wild-type (WT) Aβ1-40. To better understand the fibril-forming mechanism of the Japanese mutant peptide, we ran several long all-atom explicit water molecular dynamics simulations of the mutant and WT structures starting from NMR Alzheimer's β-amyloid fibrils (PDB-ID: 2LMN, 2LMO, 2LMP, 2LMQ). The NMR data suggest two different configurations of the fibrils consisting of either two- or three-stacks. Our WT simulations show that the two-stack model is energetically the most stable configuration; both stacks twist around their central axis in a cooperative manner to form a helical structure without any separation between strands. In contrast, monomers rapidly separate from the top and bottom of the three-stack systems. Simulations with just one-stack from either the two- or three-stack systems display the same twist motion, but monomers from the top and bottom of the stack start to separate. These observations suggest that the two-stack system is the most stable nucleation unit. Japanese mutants built for the one-stack system starting from WT protofibril models remain more stable (∼150 kcal/mol) throughout our simulations compared to the WT one-stack system. This might explain the almost instantaneous fibril formation observed for the ΔE22-Aβ1-39 mutation.