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Abstract:
Glycosylphosphatidylinositol (GPI) anchors are a unique class of complex glycolipids that anchor a great variety of proteins to the extracellular leaflet of plasma membranes of eukaryotic cells. These anchors can exist either with or without an attached protein called GPI-anchored protein (GPI-AP) both in vitro and in vivo. Although GPIs are known to participate in a broad range of cellular functions, it is to a large extent unknown how these are related to GPI structure and composition. Their conformational flexibility and micro-heterogeneity makes it difficult to study them experimentally. Simplified atomistic models are amenable to all-atom computer simulations in small lipid bilayer patches, but not suitable for studying their partitioning and trafficking in complex and heterogeneous membranes. Here, we present a coarse-grained model of GPI anchor constructed with a modified version of MARTINI force-field that is suited for modeling carbohydrates, proteins and lipids in an aqueous environment using MARTINI's polarizable water. The non-bonded interactions for sugars were re-parameterized by calculating their partitioning free energies between polar and apolar phases. In addition, sugar-sugar interactions were optimized by adjusting the second virial coefficients of osmotic pressures for solutions of glucose, sucrose and trehalose to match with experimental data. With respect to the conformational dynamics of GPI-anchored green fluoresccent protein, the accessible timescales are now at least an order of magnitude larger than for the all-atom system. This is particularly important for fine-tuning the mutual interactions of lipids, carbohydrates, and amino-acids when comparing to experimental results. We discuss the prospective use of the coarse-grained GPI model for studying protein-sorting and trafficking in membrane models.
