From mutational inactivation to aberrant gain‐of‐function: Unraveling the structural basis of mutant p53 oncogenic transition

Abstract

Various evidence has revealed that mutations in p53 exert activities that go beyond simply inactivation of wildtype functions but rather elicits downstream interactions that promote malignancy described as mutant p53 gain-of-function (GOF). Here we report the first account of the dynamics of mutation-induced structural transition of native p53 to an aberrant gain-of-function state, studying the wildtype (WT) and high incidence contact (R273C) and structural (R175H) mutant p53 (mutp53) through molecular dynamics simulation. Result analysis revealed that both mutants exhibited structural distortion and reduced flexibility, indicative of rigidity and kinetic stability. In addition, surface analysis revealed an increase in the accessible surface area in the p53 mutants. This suggests that the GOF transition involves protein unfolding and exposure of buried hydrophobic surface essential for interaction with HSF-1 oncogenic partner and wildtype p63, and p73 homologs. Further validation revealed binding cavities, similar in the mutants but dissimilar to the WT. Taken together, this study complements experimental findings and reveals the interplay between mutation-induced structural distortion, loss of flexibility, rigidity, enhanced stability, protein unfolding and ultimately, exposure of binding surfaces as conformational attributes that characterize mutP53 structure-GOF activities. This insight is, therefore, of great importance as it opens up a novel therapeutic approach toward the structure based targeting of mutP53 oncogenic involvement beyond wildtype inactivation. Furthermore, "exposed" binding site information obtained from this study can be explored for structure-based design of substances best described as "destabilizers" to disrupt the GOF interaction of mutp53.

Exploring the C‐Terminal Tail Dynamics: Structural and Molecular Perspectives into the Therapeutic Activities of Novel CRMP‐2 Inhibitors, Naringenin and Naringenin‐7‐O‐glucuronide, in the Treatment of Alzheimer's Disease

“…Hence, a high RMSD value could depict an increase in structural instability, while a low RMSD could indicate structural stability in a protein. [25,39,40] As shown in Figure 7A, the globular domain of CRMP-2 maintained high atomistic deviation in the presence of NAR and NAR-7-O-G, while the unbound form maintained structural stability.…”

“…The complexes, which include unbound, NAR-and NAR-7-O-G-bound CRMP-2, were further prepared and set up for 100 ns MD simulations using in-house protocols previously reported. [18,25,26] MD simulations were carried out using the Graphics Processing Unit (GPU) version of Particle Mesh Ewald Molecular Dynamics (PMEMD) engine in Amber 14 software package [27,28] and its integrated modules such as LEAP, to add hydrogen atoms and counter ions for neutralization at constant pH (cpH). [28,29] Likewise, the tleap module was used to generate topology files for the ligands, protein and ligand-protein complexes, while the FF14SB force field was used to define protein parameters.…”

Deciphering the canonical blockade of activated Hageman factor (FXIIa) by benzamidine in the coagulation cascade: A thorough dynamical perspective

“…This was carried out on the systems with the GPU version of AMBER 14 with an integrated PMEMD module (Grand, Götz, & Walker, ). MD simulations were performed following a standard simulation protocol, which has been reported extensively in many of our previous studies (Machaba, Cele, Mhlongo, & Soliman, ; Oguntade, Ramharack, & Soliman, ; Olotu & Soliman, ). BEN parameterization was carried out using the ANTECHAMBER module wherein atomic partial charges ((AM1BCC), gaff, using the bcc charge scheme) were generated (Salomon‐Ferrer, Götz, Poole, Le Grand, & Walker, ).…”

Exploring the effect of N308D mutation on protein tyrosine phosphatase‐2 cause gain‐of‐function activity by a molecular dynamics study

“…15 The solvent accessible solvent area (SASA) analysis was used to reveal the differences between the two systems about the exposure of buried hydrophobic core residues. 15 The solvent accessible solvent area (SASA) analysis was used to reveal the differences between the two systems about the exposure of buried hydrophobic core residues.…”

“…A very low basal catalytic activity of SHP2 is clearly enhanced in the presence of phosphopeptides with affinity for its N-SH2 domain, when specific residues located at the interface between the N-SH2 and the PTP domains are mutated. 15 Molecular dynamics (MD) simulations provide indepth details regarding the motions of individual atoms of biological macromolecules in an appropriate time scale. [12][13][14] However, the details of the increase of catalytic activity in the mutant SHP2-N308D are still unknown.…”