Conformation Dynamics of the Intrinsically Disordered Protein c-Myb with the ff99IDPs Force Field

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biology

Background:

• The intrinsically disordered protein c-Myb is crucial for cell growth and differentiation.
• Its loss leads to embryonic death due to impaired fetal blood formation.
• The conformational dynamics of c-Myb remain largely uncharacterized.

Purpose of the Study:

• To investigate the conformational dynamics of the intrinsically disordered protein c-Myb.
• To evaluate the suitability of the ff99IDPs force field for simulating c-Myb.
• To understand the folding process and identify key stabilizing elements of c-Myb.

Main Methods:

• Molecular dynamics (MD) simulations using the ff99IDPs force field.
• Comparison of ff99IDPs with ff99SBildn force field.
• Analysis of secondary chemical shifts and solvent model effects (TIP3P, TIP4P-EW, TIP5P).

Main Results:

• The ff99IDPs force field accurately reproduces diverse disordered conformers of c-Myb, including molten globule, pre-molten globule, and coil states.
• MD simulations with ff99IDPs show better agreement with experimental data than ff99SBildn.
• c-Myb undergoes a two-state folding process, initiated by tertiary and followed by helical folding, with the KEL domain acting as a folding nucleus.
• The combination of TIP3P solvent model and ff99IDPs is optimal for c-Myb conformer sampling.

Conclusions:

• The ff99IDPs force field is effective for simulating the conformational dynamics of intrinsically disordered proteins like c-Myb.
• This study elucidates the folding pathway and dynamics of c-Myb.
• The findings support the use of ff99IDPs for structure-function relationship studies in other intrinsically disordered proteins.