Martini 3 Force Field Parameters for Protein Lipidation Post-Translational Modifications.

Area of Science:

• Computational Chemistry
• Biophysics
• Molecular Dynamics

Background:

• Protein lipidations are critical post-translational modifications anchoring proteins to membranes, influencing cellular processes and disease.
• Examples include farnesylation, myristoylation, and palmitoylation, essential for proteins like Ras and actin.

Purpose of the Study:

• To develop and validate new coarse-grained Martini 3 force field parameters for key protein lipidations.
• To enable more efficient and accurate simulations of lipid-anchored proteins.

Main Methods:

• Developed parameters for cysteine-targeting farnesylation, geranylgeranylation, palmitoylation, and glycine-targeting myristoylation.
• Utilized CHARMM36m all-atom force field parameters as a reference for parameter development.
• Validated parameters through simulations of lipid-anchored peptides and proteins (Rheb, Arf1).

Main Results:

• Coarse-grained models accurately reproduced all-atom force field behavior for studied lipidations.
• Key dynamical and structural features, including solvent accessibility and membrane penetration, were reproduced.
• Validated parameters successfully simulated peripheral membrane proteins Rheb and Arf1.

Conclusions:

• The new Martini 3 parameters provide a valuable tool for simulating protein lipidations.
• These parameters facilitate the study of membrane protein dynamics, localization, and interactions.
• The developed parameters and mapping schemes are publicly available for the research community.