Molecular dynamics simulations to investigate the stability and aggregation behaviour of the amyloid-forming peptide VQIVYK from tau protein

Abstract

The formation of paired helical filaments arising from the short hexapeptide in the third repeat of tau protein, ³⁰⁶VQIVYK³¹¹, is critical for tau polymerisation. The atomic structure of the VQIVYK oligomer has revealed a dry, tightly self-complementing structure between the neighbouring β-sheet layers, termed as ‘steric zipper’. In this study, several molecular dynamics simulations with all-atom explicit water were conducted to investigate the structural stability and aggregation behaviour of the VQIVYK peptide with various sizes and its single alanine replacement mutations. Our results indicate that the van der Waals interaction between side chains of Q2, the π–π stacking interaction between aromatic rings of Y5, and the electrostatic interaction between K6 and the C-terminus play an important role in stabilising the VQIVYK oligomers within the same β-sheet layer, while hydrophobic steric zipper involving V1, I3 and Y5 is responsible for holding the neighbouring β-sheet layers together. The twisted angles of the VQIVYK oligomers were also analysed and shown to be size dependent. The present results not only provide atomic insights into amyloid formation, but are also helpful for designing new or modified capping peptides and inhibitors to prevent fibril formation of the VQIVYK peptide from tau protein.

Keywords:

• VQIVYK peptide
• tau protein
• steric zipper
• molecular dynamics simulations
• π–π stacking interaction

Acknowledgements

The authors gratefully acknowledge the financial support from the National Science Council of Taiwan (Project numbers: NSC-96-2221-E-027-045-MY3, NSC-96-2628-E-027-002-MY3 and NSC-98-2622-E-027-023-CC3), the Institute of Nuclear Energy Research of Taiwan (Project number: 992001INER072), and the National Taipei University of Technology and Taipei Medical University (Project number: NTUT-TMU-98-02).