Reconnaissance of Allostery via the Restoration of Native p53 DNA-Binding Domain Dynamics in Y220C Mutant p53 Tumor Suppressor Protein.

Allosteric regulation of protein dynamics infers a long-range deliberate propagation of information via micro- and macroscale interactions. The Y220C structural mutant is one of the most frequent cancerous p53 mutants. The mutation is distally located from the DNA-binding site of the p53 DNA-binding domain yet causes changes in DNA recognition. This system presents a unique opportunity to examine the allosteric control of mutated proteins under a drug design paradigm. We focus on the key case study of p53 Y220C mutation restoration by a series of new compounds suggested to have Y220C reactivation properties in comparison to our previous findings on the restorative potential of PK11000, a compound studied extensively for reactivation in vitro and in vivo. Previously, we implemented all-atom molecular dynamics (MD) simulations and our lab's techniques of MD-Sectors and MD-Markov state models on the wild type, the Y220C mutant, and Y220C with PK11000 to characterize the effector's restorative properties in terms of conformational dynamics and hydrogen bonding. In this study, we turn to probing the effects made by docking the battery of a new but less well-tested set of aminobenzothiazole derivative compounds reported by Baud et al., which show promise of Y220C rescue. We find that while complete and precise reconstitution of p53 WT molecular dynamics may not be observed as was the case with PK11000, dispersed local reconstitution of loop dynamics provides evidence of rescuing effects by aminobenzothiazole derivative