title: Molecular dynamics simulations of human cystatin C and its L68Q varient to investigate the domain swapping mechanism.
abstract: 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 beta-sheet (beta-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 beta2 and beta3 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 beta-region; (iii) then, the beta2-L1-beta3 hairpin structure unfolds following the so-called "zip-up" mechanism; and (iv) finally, the open form HCC is generated.
authors: Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, 1 Sec. 3 ZhongXiao E. Rd., Taipei, Taiwan 10608. f10894@ntut.edu.tw
authors: Hsuan-Liang
authors: HL
authors: Liu
authors: Yuan-Min
authors: YM
authors: Lin
authors: Jian-Hua
authors: JH
authors: Zhao
authors: Man-Ching
authors: MC
authors: Hsieh
authors: Hsin-Yi
authors: HY
authors: Lin
authors: Chih-Hung
authors: CH
authors: Huang
authors: Hsu-Wei
authors: HW
authors: Fang
authors: Yih
authors: Y
authors: Ho
authors: Wen-Yih
authors: WY
authors: Chen
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D055316:Cystatin C; D015891:Cystatins / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary
chemical_list: C525030:CST3 protein, human; D055316:Cystatin C; D015891:Cystatins