Drude Polarizable Simulations of the p53 Transactivation Domain with Different Binding Partners

Abstract

Intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDRs) do not follow the canonical structure-function paradigm of adopting a dominant fold, instead interconverting among multiple structures that are accessible along a rugged, shallow free energy surface. This structural plasticity is exploited to facilitate binding to structurally diverse partners, including both proteins and nucleic acids. Given that IDPs often serve critical regulatory roles in a range of cellular functions such as signal transduction and cell cycle checkpoints, it is crucial to understand the dynamics and interactions of these abundant proteins. Previous molecular dynamics studies of IDPs have primarily used additive force fields, which approximate polarization effects assuming a uniform dielectric medium. This approximation may fall short in IDPs, for which cooperative, induced effects such as hydrogen bonding, are particularly important in dictating the balance of secondary structure. Here, we apply the Drude-2019 polarizable protein force field for the first time to simulations of the p53 transactivation domain (TAD) alone and in complex with two binding partners: MDM2, a protein with well-defined tertiary structure, and the nuclear coactivator domain of CBP, an IDR. p53 is a widely studied protein and is a prototypical protein with IDRs, thus the TAD is a useful model IDP to examine the role of side-chain and backbone electronic polarization in the nucleation of secondary structure upon complexation. We focus our analysis on properties that are only attainable using a polarizable force field, such as individual molecular dipole moments of different protein moieties. We find that side-chain dipole moments are perturbed upon burial in the protein-protein complexes and that these depolarization effects are almost entirely confined to the interface between the p53 TAD and the binding partners, with aliphatic residues being the most impacted.