Improved Side Chain Dynamics in MARTINI Simulations of Protein–Lipid Interfaces

Specific interactions of protein
side chains and lipid membranes
regulate the localization, orientation, and activity of many peripheral
proteins. Here, we introduce a modification of the coarse-grained
MARTINI protein model, called ‘side chain fix’ (scFix), that
was necessary and sufficient to correctly sample the side chain dynamics
of β-strands in several globular proteins. When compared to
μs long atomistic simulations or previous experimental findings,
scFix MARTINI simulations reproduced all key interactions between
the well-studied PLC-δ1 pleckstrin homology domain and a phosphatidylinositol-4,5-bisphosphate
(PIP2) containing lipid membrane. Moreover, the extended runtime and
higher sampling speed enabled the systematic mapping of the protein’s
rolling motion at the membrane, the identification of short-lived
and stable binding orientations, as well as the verification and prediction
of already known and of novel transient PIP2 binding sites. scFix
also showed promise to maintain proper side chain orientation in other
secondary structural motifs of the α-spectrin SH3 domain, the
B1 domain of protein G, and the villin headpiece. This suggests that
scFix improves on the predictive power of MARTINI simulations regarding
protein–lipid and protein–ligand interactions.