Hydrophobicity in Intrinsically Disordered Protein Force Fields: Implications for Conformational Ensembles and...

Area of Science:

• Biophysics
• Computational Biology
• Protein Science

Background:

• Intrinsically disordered proteins (IDPs) lack stable 3D structures, posing simulation challenges.
• Accurate modeling of water-protein interactions is crucial for IDPs and protein association.

Purpose of the Study:

• Compare hydrophobicity and water-protein interactions across three molecular dynamics (MD) force fields: amber03ws (a03ws), CHARMM36m (C36m), and a99SB-disp.
• Evaluate the impact of force field choice on the behavior of an aggregation-prone tau fragment (jR2R3 P301L).

Main Methods:

• Utilized indirect umbrella sampling (INDUS) to quantify amino acid dewetting free energies.
• Analyzed water structuring via water triplet angle distribution and measured water diffusion in hydration shells.
• Performed MD simulations of a tau fragment (jR2R3 P301L) using different force fields.

Main Results:

• CHARMM36m exhibited the lowest dewetting free energies (highest hydrophobicity), while a99SB-disp showed the highest (lowest hydrophobicity).
• Water diffusion was slowest in a99SB-disp hydration shells due to distinct water structuring (e.g., tetrahedral coordination).
• CHARMM36m promoted dimer formation via lower dewetting free energies; a99SB-disp dimerization was influenced by favorable water structure changes.

Conclusions:

• Force field choice significantly impacts water-protein interactions and IDP behavior, including aggregation.
• Dewetting free energies and water structuring metrics are valuable for developing new force fields for IDPs.
• Accurate modeling of water-protein interactions is essential for understanding IDP function and dysfunction.