title: Improved Side Chain Dynamics in MARTINI Simulations of Protein-Lipid Interfaces.
abstract: 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.
authors.affiliation: Laboratory of Applied Mechanobiology, Department of Health Sciences and Technology, ETH Zurich , Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland.
authors.forename: Florian A
authors.initials: FA
authors.lastname: Herzog
authors.affiliation: Laboratory of Applied Mechanobiology, Department of Health Sciences and Technology, ETH Zurich , Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Braun
authors.affiliation: Laboratory of Applied Mechanobiology, Department of Health Sciences and Technology, ETH Zurich , Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland.
authors.forename: Ingmar
authors.initials: I
authors.lastname: Schoen
authors.affiliation: Laboratory of Applied Mechanobiology, Department of Health Sciences and Technology, ETH Zurich , Vladimir-Prelog-Weg 4, 8093 Zurich, Switzerland.
authors.forename: Viola
authors.initials: V
authors.lastname: Vogel
mesh_terms: D056004:Molecular Dynamics Simulation; D018129:Phosphatidylinositol Phosphates / Q000737:chemistry* / Q000378:metabolism*; D054803:Phospholipase C delta / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary
chemical_list: D018129:Phosphatidylinositol Phosphates; C060980:phosphatidylinositol 3,4-diphosphate; D054803:Phospholipase C delta