Nonbonded Parameter Optimization Improving Simulation of Intrinsically Disordered Phosphoproteins.

Area of Science:

• Biochemistry and Molecular Biology
• Computational Chemistry
• Structural Biology

Background:

• Phosphorylated proteins are vital regulators in cellular signaling, expansion, and biochemical reactions.
• Molecular dynamics (MD) simulations are essential for studying phosphoprotein dynamics.
• Existing force fields often inaccurately represent phosphoprotein radii of gyration (Rg).

Purpose of the Study:

• To develop and validate an improved molecular dynamics force field for phosphoproteins.
• To enhance the accuracy of Rg and chemical shift predictions for phosphorylated proteins.
• To investigate the conformational properties of phosphoproteins using MD simulations.

Main Methods:

• Reoptimization of vdW radius for oxygen and phosphorus atom charges using a reweighting algorithm and thermodynamic integration.
• Development of the phosRg force field.
• Validation against experimental data for seven representative phosphoproteins.
• Assessment of the TIP4P-D solvent model for phosphoprotein simulations.

Main Results:

• The phosRg force field shows improved agreement with experimental Rg and chemical shift compared to phosaa10.
• phosRg simulations yield more extended phosphoprotein conformations.
• phosRg simulations exhibit reduced hydrophobic interactions and hydrogen bonds compared to phosaa10.
• The TIP4P-D solvent model is compatible with phosRg for simulating phosphorylated proteins.

Conclusions:

• The dual-objective optimization strategy effectively improves force field parameters for phosphoproteins.
• phosRg offers a more accurate representation of phosphoprotein dynamics and conformations.
• phosRg is recommended for future simulations of phosphorylated proteins and related systems.