A coarse-grained model for simulations of phosphorylated disordered proteins

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Protein phosphorylation is a crucial post-translational modification regulating protein function.
• Intrinsically disordered proteins (IDPs) are frequently phosphorylated, impacting their interactions and activities.
• Understanding phosphorylation's effect on IDP conformational ensembles is vital for elucidating biophysical mechanisms.

Purpose of the Study:

• To develop a coarse-grained molecular dynamics model for simulating phosphorylation effects on IDPs.
• To investigate how serine and threonine phosphorylation influence the global structural properties of disordered proteins.
• To determine the primary drivers of structural changes induced by phosphorylation in IDPs.

Main Methods:

• Developed a data-driven, coarse-grained molecular dynamics model compatible with the CALVADOS protein simulation framework.
• Parameterized the model using experimental data on phosphorylation-induced changes in protein dimensions.
• Compared simulation results with baseline models and simulations using phosphomimetic amino acids (aspartate, glutamate).

Main Results:

• The developed model accurately captures phosphorylation-induced alterations in disordered protein global dimensions.
• Phosphorylation's impact on the global dimensions of disordered proteins is predominantly attributed to the introduction of additional charge.
• Simulations using phosphomimetics confirmed the charge-driven nature of these structural modifications.

Conclusions:

• The coarse-grained model provides a valuable tool for studying phosphorylation in disordered proteins at a proteome scale.
• Phosphorylation-induced charge is the main determinant of global structural changes in disordered proteins.
• This model can advance research into protein phosphorylation's role in biological processes like phase separation.