Atomistic simulations reveal structural disorder in the RAP74-FCP1 complex

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• The RAP74-FCP1 complex is crucial for dephosphorylating RNA polymerase II, a key step before transcription initiation.
• Understanding this interaction is vital for deciphering gene regulation mechanisms.

Purpose of the Study:

• To characterize the atomic details of the RAP74-FCP1 interaction using molecular dynamics simulations.
• To investigate how intrinsically disordered proteins bind to structured domains and the implications for complex stability.

Main Methods:

• Atomically detailed molecular dynamics simulations.
• Analysis of protein-protein interactions, focusing on structural changes and hydrophobic contacts.

Main Results:

• The intrinsically disordered FCP1 C-terminal forms an amphipathic helix upon binding to RAP74.
• The interaction reorganizes and stabilizes the RAP74 winged helix domain.
• Significant flexibility, termed "dynamic fuzziness," persists in FCP1 even after binding.

Conclusions:

• Hydrophobic contacts are critical for stabilizing disordered protein complexes.
• Winged helix domains utilize specific mechanisms for binding disordered partners.
• FCP1 binding to RAP74 involves a coupled folding-binding transition with minimal conformational entropy loss, suggesting a less abrupt transition than previously assumed.