Electronic Polarization at the Interface between the p53 Transactivation Domain and Two Binding Partners

Intrinsically disordered proteins (IDPs) are an abundant class of highly charged proteins that participate in numerous crucial biological processes, often in regulatory roles. IDPs do not have one major free energy minimum with a dominant structure, instead existing as conformational ensembles of multiple semistable conformations. p53 is a prototypical protein with disordered regions and binds to many structurally diverse partners, making it a useful model for exploring the role of electrostatic interactions at IDP binding interfaces. In this study, we used the Drude-2019 force field to simulate the p53 transactivation domain with two protein partners to probe the role of electrostatic interactions in IDP protein-protein interactions. We found that the Drude-2019 polarizable force field reasonably reproduced experimental chemical shifts of the p53 transactivation domain (TAD) in one complex for which these data are available. We also found that the proteins in these complexes displayed dipole response at specific residues of each protein and that residues primarily involved in binding showed a large percent change in dipole moment between the unbound and complexed states. Probing the role of electrostatic interactions in IDP binding can allow us greater fundamental understanding of these interactions and may help with targeting p53 or its partners for drug design.

Automated summary

Intrinsically disordered proteins (IDPs) are abundant and play crucial regulatory roles in biological processes. This study used the Drude-2019 force field to simulate the interactions between the p53 transactivation domain and two protein partners, revealing the importance of electrostatic interactions in IDP protein-protein interactions.