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.

The transient manifold structure of the p53 extreme C-terminal domain: insight into disorder, recognition, and binding promiscuity by molecular dynamics simulations

“…A high degree of helicity in the unbound p53-CTD was described in a recently published computational work. 60 Such strong conformational propensity is inconsistent with circular dichroism data 24,60 and could be due not only to force field limitations, but also to the choice of starting structures derived from the S100B(bb) bound conformation. 60 In 30.7% of the helical structures, the residual helicity spans the 381 KKL 383 stretch.…”

“…60 Such strong conformational propensity is inconsistent with circular dichroism data 24,60 and could be due not only to force field limitations, but also to the choice of starting structures derived from the S100B(bb) bound conformation. 60 In 30.7% of the helical structures, the residual helicity spans the 381 KKL 383 stretch. In all other cases, single helical turns are observed in the disordered, and unbound N-terminal tail, often in addition to the helical turn at 381 KKL 383 .…”

“…Indeed, existing NMR 23 and CD 60 data show that the p53-CTD section is highly disordered when unbound in solution. Nevertheless, based on the information discussed in this work, experimental support for the MoRF-driven molecular recognition mechanism could be obtained by biasing the conformational ensemble towards specific structural MoRFs by means, for example, of stapling the peptide.…”

Molecular dynamics coupled with a virtual system for effective conformational sampling

“…Ikebe et al reported that the larger the value of becomes, the smaller the helical propensity in the resultant conformational ensemble at 300 K . Iida et al set to investigate a free‐energy landscape of the C‐terminal domain of p53, which is an intrinsically disordered segment . We also set for the current study.…”

“…In the sampling, we introduced a virtual variable that has a role in confining the conformation in the zone: i.e., the molecular system (real system) interacts with a “virtual system,” which is an abstract and unrealistic system defined by the virtual variable . This technique, named V‐McMD, was combined with McMD . Similarly, the virtual system was combined with AUS and was designated as a virtual‐system coupled AUS (V‐AUS) .…”