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

Abstract

Alzheimer's disease (AD) has been identified as a progressive, neurodegenerative disorder associated with protein misfolding due to the aggregation of monomeric β-amyloid proteins (Aβ) to form fibrillar plaques. Experimental attempts to purify and chemically analyze the structure of Aβ protofibrils and to 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 the 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 have ran several long (μs) all atom explicit water molecular dynamics simulations of the mutant and WT peptide starting from the random-coil structure at two different temperatures (310 and 350 K). Our simulations showed that the ΔE22-Aβ1-39 mutant formed a stable semi-helical hairpin structure about 5 times faster than the WT. The helical hairpin conformation was less evident in WT trajectory and was quickly unfolded (particularly at 310K). The RMSF plots showed similar patterns of fluctuations in both the WT and mutant backbone atoms. However, the deletion of the E22 lowered the fluctuations of the mutant structure by about 2A at 310K. This fast and stable conformational change in ΔE22-Aβ1-39 can be used as a seed for the rapid fibril formation as observed in the experimental studies.