Molecular dynamics simulations of human cystatin C and its L68Q varient to investigate the domain swapping mechanism

Hsuan Liang Liu, Yuan Min Lin, Jian Hua Zhao, Man Ching Hsieh, Hsin Yi Lin, Chih Hung Huang, Hsu Wei Fang, Yih Ho, Wen Yin Chen

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


Human cystatin C variant (L68Q), one of the amyloidgenic proteins, has been shown to form dimeric structure spontaneously via domain swapping and easily cause amyloid deposits in the brains of patients suffering from Alzheimer's disease or hereditary cystatin C amyloid angiopathy. The monomeric L68Q and wild-type (wt) HCCs share similar structural feature consisting of a core with a five-stranded anti-parallel β-sheet (β-region) wrapped around a central helix. In this study, various molecular dynamics simulations were conducted to investigate the conformational fluctuations of the monomeric L68Q and wt HCCs at various combinations of temperature (300 and 500K) and pH (2 and 7) to gain insights into the domain swapping mechanism. The results show that elevated temperature accelerates the disruption of the hydrophobic core and acidic condition promotes the destruction of three salt bridges between β2 and β3 in both HCCs. The results also indicate that the interior hydrophobic core of the L68Q variant is relatively unstable, leading to domain swapping more readily comparing to wt HCC under conditions favoring this process. However, these two monomeric HCCs adopt the same mechanism of domain swapping as follows: (i) first, the interior hydrophobic core is disrupted; (ii) subsequently, the central helix departs from the β-region; (iii) then, the β2-L1-β3 hairpin structure unfolds following the so-called "zip-up" mechanism; and (iv) finally, the open form HCC is generated.

Original languageEnglish
Pages (from-to)135-144
Number of pages10
JournalJournal of Biomolecular Structure and Dynamics
Issue number2
Publication statusPublished - Oct 2007


  • Alzheimer's disease
  • Domain swapping
  • Hereditary cystatin C amyloid angiopathy
  • Human cystatin C
  • Hydrophobic core
  • Molecular dynamics simulation
  • Zip-up

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology


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