Modeling the Relationship between the p53 C-Terminal Domain and Its Binding Partners Using Molecular Dynamics

Abstract

Fifty percent of all cancer cases result from mutations of the TP53 gene, which encodes the tumor suppressor p53, and it is hypothesized that the p53-mediated checkpoint pathway is compromised in most of the remaining cases. The p53 C-terminal domain (CTD) is an important site of p53 regulation but by nature is difficult to study, as it is intrinsically disordered. In this study, we performed molecular dynamics simulations on the p53 CTD and five known regulatory binding partners. We identified distinct trends in fluctuation within and around the p53 CTD binding site on each partner demonstrating a behavior that facilitates association. Further, we present evidence that the size of the hydrophobic pocket in each p53 CTD binding site governs the secondary structure of the p53 CTD when in the bound state. This information will be useful for predicting new binding partners for the p53 CTD, identifying interacting regions within other known partners, and discovering inhibitors that provide additional points of control over p53 activity.

Binding of Two Intrinsically Disordered Peptides to a Multi-Specific Protein: A Combined Monte Carlo and Molecular Dynamics Study

“…The MC simulations of p53 also produce a small population of -hairpins, albeit typically more fully formed, resulting in a shift of the peak to around 7.5 Å (see Figure 1A). We note that the tendency for the free p53 peptide to form -hairpin-like structures was also observed in the MD study of Allen et al [22]. Overall, we find that both the free p53 and TRTK-12 peptides sample multiple conformations, including transient -helical structures.…”

Potential Conformational Heterogeneity of p53 Bound to S100B(ββ)

“…For example, p53-NRD was found to be very flexible and to unfold significantly in the bound state during a 20-ns explicit solvent simulation in the Amber ff99 force field 31 . Allen et al found that the Cterminus of p53-NRD unfolded during one of their 100-ns explicit solvent simulations in the GROMOS 53a6 force field 34 . We have further verified the force field dependence using an additional 100-ns simulation of the complex in the Amber ff99SB force field 43 , which is arguably one of the best force fields optimized for simulating protein conformational equilibria 46 .…”

Molecular dynamics of the full-length p53 monomer

“…[101][102][103][104] MD conformational analyses were also performed for the N-terminal recognition α helix, [105][106][107][108] and for C-terminal fragments. 109,110 In order to study the entire monomeric protein behavior and its inter domain interactions, we have built a model for the full-length p53 (residues 1-393). The structure of unresolved fragments (10%) and disordered links between the domains have been predicted and merged with the experimental data.…”