Dynamic perspectives into the mechanisms of mutation‐induced p53‐DNA binding loss and inactivation using active perturbation theory: Structural and molecular insights toward the design of potent reactivators in cancer therapy

Abstract

The DNA-binding ability of p53 represents the crux of its tumor suppressive activities, which involves transcriptional activation of target genes responsible for apoptosis and cell-cycle arrest. Mutational occurrences within or in close proximity to the DNA-binding surface of p53 have accounted for the loss of direct DNA-binding ability and inactivation implicated in many cases of cancer. Moreover, the design of therapeutic compounds that can restore DNA-binding ability in p53 mutants has been identified as a way forward in curtailing their oncogenic activities. However, there is still the need for more insights into evaluate the perturbations that occur at the DNA-binding interface of mp53 relative to DNA-binding loss, inactivation, and design of potent reactivators, hence the purpose of this study. Therefore, we evaluated p53-structural (R175H) and contact (R273C) mutational effects using tunnel perturbation analysis and other computational tools. We identified significant perturbations in the active tunnels of p53, which resulted in altered geometry and loss, unlike in the wild-type p53. This corroborated with structural, DNA-binding, and interaction network analysis, which showed that loss of flexibility, repulsion of DNA-interactive residues, and instability occurred at the binding interface of both mutants. Also, these mutations altered bonding interactions and network topology at the DNA-binding interface, resulting in the reduction of p53-DNA binding proximity and affinity. Therefore, these findings would aid the structure-based design of novel chemical entities capable of restoring p53-DNA binding and activation.

Halting ionic shuttle to disrupt the synthetic machinery—Structural and molecular insights into the inhibitory roles of Bedaquiline towards Mycobacterium tuberculosis ATP synthase in the treatment of tuberculosis

“…2D, two-dimensional; ATP, adenosine triphosphate; BDQ, bedaquiline according to standard simulation protocols, which has been previously adopted in previous studies and enumerated as follows. [32][33][34][35][36] Parameterization of the inhibitor was carried out using the ANTECHAMBER module wherein atomic partial charges (AM1BCC) gaff, using the bcc charge scheme were generated. 37 The FF14SB AMBER force field 38 was then used to parameterize the protein.…”

CF3‐Pyridinyl Substitution on Antimalarial Therapeutics: Probing Differential Ligand Binding and Dynamical Inhibitory Effects of a Novel Triazolopyrimidine‐Based Inhibitor on Plasmodium falciparum Dihydroorotate Dehydrogenase

“…The structural arrangements within an enzyme structure strongly correlate with its biological roles. As such any structural alterations or perturbations on the structural integrity of an enzyme could have a consequential effect on its functions as well . The mechanism of action of many small molecule inhibitors involves binding to and distorting implicated enzymes in disease pathways, hence the need to access the structural dynamics and conformational changes associating with the differential inhibitory activities of both DSM421 and DSM265.…”

The pivot point arginines identified in the β-pinwheel structure of C-terminal domain from Salmonella Typhi DNA Gyrase A subunit

“…The final step of explicit water refinement resulted in structures clustered using pairwise backbone root-mean-square deviation (r.m.s.d.) at the protein-DNA binding interface 36,37 . The clusters were evaluated and ranked based on average interactive energies including van der Waals, electrostatic and AIR energies.…”