Molecular dynamics simulations and free energy analyses on the dimer formation of an amyloidogenic heptapeptide from human β2-microglobulin: Implication for the protofibril structure

Hongxing Lei, Chun Wu, Zhixiang Wang, Yong Duan

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28 Scopus citations

Abstract

Amyloid formation is associated with many neurodegenerative diseases. Recent findings suggest that early oligomeric aggregates could be major sources of toxicity. We present a computational investigation of the first step of amyloid initiation-dimer formation of a seven residue peptide (NHVTLSQ) from human β2-microglobulin at pH 2.0, which renders +2.0 units charges to each peptide. A total of over 1.2 μs of simulations with explicit solvent and 1.0 μs of simulations with implicit solvent were conducted. Main-chain conformational restraint was applied to facilitate the formation of ordered dimers. An antiparallel β-sheet with six main-chain hydrogen bonds was dominant in the implicit solvent simulations. In contrast, no stable dimers were observed in the two negative controls, the mouse heptapeptide (KHDSMAE, +3.0 units charges) and the scrambled human heptapeptide (QVLHTSN). Explicit solvent simulations presented a more complex scenario. The wild-type human heptapeptide formed predominantly antiparallel β-sheets (∼38%) although parallel ones (∼12%) were also observed. Hydrophobic contacts preceded hydrogen bond saturation in the majority of the association events in the explicit solvent simulations, highlighting the important role of hydrophobic interaction in amyloid initiation. The fact that the mouse dimer dissociated immediately after the removal of conformational restraint suggests that the higher conformational entropy barrier, along with the stronger charge repulsion and weaker hydrophobic interaction, contributed to its inability to form amyloid fibril. The closeness of positive charge pairs in the dimers of the scrambled human heptapeptide may prohibit further β-sheet extension and fibril growth. Combining the results from simulations and free energy analyses, we propose that the building block for this amyloid fibril is an antiparallel dimer with a two-residue register shift and six main-chain hydrogen bonds. A double-layer protofibril structure is also proposed in which two antiparallel β-sheets face each other and are held together by hydrophobic staples and hydrogen bonds of the polar side-chains.

Original languageEnglish (US)
Pages (from-to)1049-1063
Number of pages15
JournalJournal of Molecular Biology
Volume356
Issue number4
DOIs
StatePublished - Mar 3 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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