title: Variation of free-energy landscape of the p53 C-terminal domain induced by acetylation: Enhanced conformational sampling.
abstract: The C-terminal domain (CTD) of tumor suppressor protein p53 is an intrinsically disordered region that binds to various partner proteins, where lysine of CTD is acetylated/nonacetylated and histidine neutralized/non-neutralized. Because of the flexibility of the unbound CTD, a free-energy landscape (FEL) is a useful quantity for determining its statistical properties. We conducted enhanced conformational sampling of CTD in the unbound state via virtual system coupled multicanonical molecular dynamics, in which the lysine was acetylated or nonacetylated and histidine was charged or neutralized. The fragments were expressed by an all-atom model and were immersed in an explicit solvent. The acetylation and charge-neutralization varied FEL greatly, which might be convenient to exert a hub property. The acetylation slightly enhanced alpha-helix structures that are more compact than sheet/loop conformations. The charge-neutralization produced hairpins. Additionally, circular dichroism experiments confirmed the computational results. We propose possible binding mechanisms of CTD to partners by investigating FEL. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.
authors.affiliation: Institute for Protein Research Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Iida
authors.affiliation: Technology Research Association for Next Generation Natural Products Chemistry, 2-3-26 Aomi, Koto-Ku, Tokyo, 135-0064, Japan.|IMSBIO Co, Ltd, Owl Tower 6F, 4-21-1, Higashi-ikebukuro, Toshima-ku, Tokyo, 170-0013, Japan.
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Mashimo
authors.affiliation: Technology Research Association for Next Generation Natural Products Chemistry, 2-3-26 Aomi, Koto-Ku, Tokyo, 135-0064, Japan.|Hitachi Solutions East Japan, 21-1 Ekimaehoncho, Kawasaki-ku, Kanagawa, 210-0007, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kurosawa
authors.affiliation: Institute for Protein Research Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Hojo
authors.affiliation: Institute for Protein Research Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Muta
authors.affiliation: Institute for Protein Research Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Goto
authors.affiliation: Technology Research Association for Next Generation Natural Products Chemistry, 2-3-26 Aomi, Koto-Ku, Tokyo, 135-0064, Japan.|Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), 2-3-36, Aomi, Koto-ku, Tokyo, 135-0064, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Fukunishi
authors.affiliation: Institute for Protein Research Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Institute for Protein Research Osaka University, 3-2 Yamadaoka, Suita, Osaka, 565-0871, Japan. higo@protein.osaka-u.ac.jp.
authors.forename: Junichi
authors.initials: J
authors.lastname: Higo
mesh_terms: D002942:Circular Dichroism; D006801:Humans; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D000072417:Protein Domains; D013816:Thermodynamics; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53
keywords: free energy landscape; intrinsically disordered; multicanonical; p53 C-terminal; post-translation modification