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

Protein lipidations are vital co/post-translational modifications
that tether lipid tails to specific protein amino acids, allowing
them to anchor to biological membranes, switch their subcellular localization,
and modulate association with other proteins. Such lipidations are
thus crucial for multiple biological processes including signal transduction,
protein trafficking, and membrane localization and are implicated
in various diseases as well. Examples of lipid-anchored proteins include
the Ras family of proteins that undergo farnesylation; actin and gelsolin
that are myristoylated; phospholipase D that is palmitoylated; glycosylphosphatidylinositol-anchored
proteins; and others. Here, we develop parameters for cysteine-targeting
farnesylation, geranylgeranylation, and palmitoylation, as well as
glycine-targeting myristoylation for the latest version of the Martini
3 coarse-grained force field. The parameters are developed using the
CHARMM36m all-atom force field parameters as reference. The behavior
of the coarse-grained models is consistent with that of the all-atom
force field for all lipidations and reproduces key dynamical and structural
features of lipid-anchored peptides, such as the solvent-accessible
surface area, bilayer penetration depth, and representative conformations
of the anchors. The parameters are also validated in simulations of
the lipid-anchored peripheral membrane proteins Rheb and Arf1, after
comparison with independent all-atom simulations. The parameters,
along with mapping schemes for the popular martinize2 tool, are available for download at 10.5281/zenodo.7849262 and also as supporting information.