Drude Polarizable Force Field for Phosphorylated Polypeptides and Proteins

Area of Science:

• Biochemistry
• Computational Biology
• Structural Biology

Background:

• Phosphorylation is a key post-translational modification regulating protein function.
• Modeling phosphorylated residues in simulations is challenging due to their charged nature.
• Accurate force fields are needed to study phosphorylation's impact on protein structure.

Purpose of the Study:

• To develop and validate new force field parameters for phosphorylated serine, threonine, and tyrosine.
• To enable accurate molecular dynamics simulations of phosphorylated proteins.
• To investigate the structural effects of phosphorylation on proteins and polypeptides.

Main Methods:

• Parametrization of force fields using quantum mechanical properties.
• Validation in full-length proteins (ERK2, WNK1) and short polypeptides.
• Analysis of interactions and conformational changes.

Main Results:

• Developed and validated force field parameters for phosphorylated amino acids in all protonation states.
• Observed strong interactions with lysine and arginine, rigidifying protein loops.
• Found reduced disorder and increased alpha-helical turns in phosphorylated polypeptides.

Conclusions:

• The new force field parameters accurately represent phosphorylated residues in simulations.
• This work facilitates the study of phosphorylation-induced conformational changes, especially in intrinsically disordered proteins.
• The parameters are compatible with the Drude protein force field, expanding its utility.