Capturing Choline-Aromatics Cation-π Interactions in the MARTINI Force Field.

Area of Science:

• Biophysics
• Computational Biology
• Molecular Dynamics

Background:

• Cation-π interactions are vital for biomolecular recognition, particularly between membrane lipids and proteins.
• Existing coarse-grain (CG) force fields, like MARTINI, often underestimate these crucial interactions.
• Accurate simulation of peripheral membrane protein binding requires precise modeling of these forces.

Purpose of the Study:

• To modify the polarizable MARTINI CG model to accurately capture cation-π interactions.
• To enable reliable simulation of peripheral protein membrane association driven by aromatic amino acid-choline interactions.
• To develop an improved CG model, MARTINI 2.3P, for membrane protein simulations.

Main Methods:

• Curated a dataset of eight peripheral proteins.
• Adjusted parameters in the polarizable MARTINI force field to improve cation-π interactions.
• Validated binding events against all-atom simulations and experimental data.
• Performed negative controls and checked membrane properties and translocation potentials.

Main Results:

• The standard MARTINI CG model underestimated aromatics-choline interactions and failed to reproduce protein binding.
• Adjustments to the polarizable MARTINI force field significantly improved the modeling of membrane binding events.
• Protein orientations and binding were accurately reproduced, validated by reference data.
• The modified model (MARTINI 2.3P) showed no adverse effects on membrane properties or translocation.

Conclusions:

• The enhanced MARTINI 2.3P model accurately simulates cation-π interactions essential for peripheral protein-membrane association.
• This improved model is suitable for studying membrane proteins, including peripheral ones, and their binding mechanisms.
• MARTINI 2.3P represents a significant advancement for coarse-grain simulations of membrane protein interactions.