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

Area of Science:

• Biochemistry and Molecular Biology
• Computational Biology
• Structural Biology

Background:

• Intrinsically disordered proteins (IDPs) are vital for biological regulation and lack stable structures, existing as dynamic ensembles.
• The p53 protein, with disordered regions, serves as a model for studying protein-protein interactions due to its diverse binding partners.
• Understanding electrostatic interactions is key to deciphering IDP function and developing targeted therapies.

Purpose of the Study:

• To investigate the role of electrostatic interactions in intrinsically disordered protein (IDP) binding using molecular simulations.
• To explore the binding interface of the p53 transactivation domain (TAD) with two protein partners.
• To assess the utility of the Drude-2019 force field in modeling IDP complexes.

Main Methods:

• Utilized the Drude-2019 polarizable force field for molecular dynamics simulations.
• Simulated the p53 transactivation domain (TAD) in complex with two distinct protein partners.
• Validated simulation accuracy by comparing with experimental chemical shift data.

Main Results:

• The Drude-2019 force field accurately reproduced experimental chemical shifts for the p53 TAD in a known complex.
• Simulations revealed significant dipole response at specific residues within the interacting proteins.
• Residues critical for binding exhibited substantial changes in dipole moment upon complex formation.

Conclusions:

• Electrostatic interactions, particularly dipole responses, play a significant role in IDP-protein binding.
• The Drude-2019 force field is a suitable tool for studying electrostatic contributions in IDP interactions.
• Insights gained can inform drug design strategies targeting IDPs like p53 and their partners.