title: Insights into the conformational changes of several human lysozyme variants associated with hereditary systemic amyloidosis.
abstract: In this study, various ethanol- and temperature-induced molecular dynamics simulations were conducted to investigate the conformational changes of several human lysozyme variants (I56T, D67H, and T70N) associated with hereditary systemic amyloidosis. The results show that these variants are all more sensitive to conditions affecting the structural integrity of this protein. The structural analyses of these variants reveal a high population of more unstable beta-domain and distorted hydrophobic core compared to the wild-type human lysozyme, particularly for the two natural amyloidogenic variants D67H and I56T. For the D67H variant, the distance between the mass centers of residues 54 and 67 was found to elongate as a result of the destruction of the hydrogen-bonding network stabilizing the two long loops in the beta-domain. It further accelerates the unfolding of this variant, starting from the hydrophobic core between the alpha- and beta-domains. For the I56T variant, the introduction of a hydrophilic residue in the hydrophobic core directly destroys the native contacts in the alpha-beta interface, leading to fast unfolding. The present results are consistent with the previous hypothesis suggesting that the distortion of the hydrophobic core at the alpha-beta interface putatively results in the formation of the initial "seed" for amyloid fibrils.
authors.affiliation: Department of Chemical Engineering and Biotechnology and Graduate Institute of Biotechnology, National Taipei University of Technology, 1 Sec. 3 ZhongXiao E. Rd., Taipei, Taiwan.
authors.forename: Hsuan-Liang
authors.initials: HL
authors.lastname: Liu
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Wu
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Zhao
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Liu
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Huang
authors.forename: Hsu-Wei
authors.initials: HW
authors.lastname: Fang
authors.forename: Yih
authors.initials: Y
authors.lastname: Ho
mesh_terms: D028226:Amyloidosis, Familial / Q000235:genetics* / Q000378:metabolism*; D003198:Computer Simulation; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D009113:Muramidase / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011487:Protein Conformation
chemical_list: D009113:Muramidase