Molecular Dynamics Simulations of Human FOXO3 Reveal Intrinsically Disordered Regions Spread Spatially by...

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• The transcription factor FOXO3 is crucial for cellular functions and targeted in anti-cancer and anti-aging therapies.
• FOXO3 is predominantly an intrinsically disordered protein (IDP), with limited structural knowledge outside its DNA-binding domain hindering function-structure understanding.

Purpose of the Study:

• To investigate the structural properties and dynamics of the FOXO3 protein, particularly its intrinsically disordered regions.
• To understand how the structure of FOXO3 facilitates its molecular interactions and cellular functions.

Main Methods:

• Extensive molecular dynamics (MD) simulations of the entire FOXO3/DNA complex using implicit solvation models.
• Accelerated MD simulations under explicit solvent conditions for a key central region (FOXO3^120-530).
• Introduction and application of a novel graphical tool, the Local Compaction Plot (LCP), for visualizing IDP structural diversity.

Main Results:

• Simulations confirm FOXO3's highly disordered nature, revealing varying degrees of folding propensity.
• Two linker regions adjacent to the DNA-binding domain were observed in an unexpectedly extended conformation.
• This extended conformation is attributed to electrostatic repulsion between connected domains, not amino acid sequence.

Conclusions:

• FOXO3 exists as an intrinsically disordered protein in an unusually extended conformation.
• This extended structure is a functional adaptation to enhance interactions with molecular partners.
• The findings provide critical insights into the structure-function relationship of FOXO3, relevant for therapeutic development.