Surface Interactions Restricts Amyloid-β Peptides Movements Resulting in their Rapid Self-Assembly into β Sheets; a Molecular Dynamics Study

Abstract

Alzheimer's Disease (AD) is an important and increasingly prevalent neurodegenerative disease in the United State. According to the amyloid hypothesis, formation of soluble oligomers and eventually fibrils composed of neurodegenerative amyloid beta (Aβ) peptides in the brain is the etiological agent of AD. While the macro level causes of AD are somewhat understood, the molecular interactions that lead to the formation of fibrils from individual Aβ peptides are not well understood. It has been shown experimentally that Aβ peptides self assemble to form fibrils on 2D surfaces at much faster rates than they form fibrils in the 3D environment of solutions. However, the molecular mechanism of the fibril formation on 2D surfaces and the effect of surface chemistry on the speed and extent of fibril formation remain unknown. We have run long molecular dynamics simulations of Aβ (1-40) monomers on Alkanethiol self-assembled monolayers (SAM) with different functional head groups (-CH3, -OH) and also in bulk water solution. Our simulations showed that SAM-CH3 adsorbs Aβ monomers quickly, restricting their motion and resulting in inter-monomer β-sheet formation in orders of 10s of nanoseconds. The same effect was not observed in bulk solution, even though those simulations ran for a time one order of magnitude longer than SAM-monomer simulations. Unlike the SAM-CH3 surface, Aβ-monomer adsorption on SAM-OH surface was weak, leading the monomers to leave the surface and move into the solution. These results indicate the importance of hydrophobic interactions for mediating Aβ self-assembly on the SAM. These simulations help us to better understand the aggregation and toxicity mechanism of Aβ peptides in more physiologically relevant surfaces such as lipid bilayers, which have been shown to interact with amyloids to modulate fibrillation.