Variation of free‐energy landscape of the p53 C‐terminal domain induced by acetylation: Enhanced conformational sampling. Issue 31 (13th October 2016)

• Record Type: Journal Article
• Authors: Iida, Shinji; Mashimo, Tadaaki; Kurosawa, Takashi; Hojo, Hironobu; Muta, Hiroya; Goto, Yuji; Fukunishi, Yoshifumi; Nakamura, Haruki; Higo, Junichi
• Is Part Of: Journal of computational chemistry. Volume 37:Issue 31(2016)
• Page Start: 2687
• Page End: 2700
• Publication Date: 2016-10-13
• Subjects: free energy landscape -- p53 C‐terminal -- intrinsically disordered -- post‐translation modification -- multicanonical; Chemistry -- Data processing -- Periodicals; 542.85
• DOI: 10.1002/jcc.24494
• Languages: English
• ISSNs: 0192-8651

Abstract

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. Abstract : The effects of acetylation is demonstrated on the conformational ensemble of the p53 C‐terminal domain, by computing free‐energy landscapes. The landscapes show that the acetylation varies largely with the conformational ensemble: enhancement of helicity and hydrophobic core formation. The hub property of p53 is discussed by analyzing the free‐energy landscape.