Glycosylphosphatidyl-Inositols (GPIs) are complex anchoring devices to attach proteins to the outer leaflet of membranes in eukaryotic cells. The spectrum of possible functions that especially the glycan part of the anchor might convey is still highly debated, in part because no clear molecular scale picture exists of how the anchor- and hence the attached protein- is arranged with respect to the lipid head group region. We have created a computational model of GPI-anchored green fluorescent protein (GFP) by joining lipids, carboyhdrates and amino acids by state-of-the-art force fields from the Amber family. The transition from the di-acylglycerol (Lipid14) to the glycan part (GLYCAM06) is accomplished via a hybrid, explicitly parametrized hub involving the phosphate group and inositol; for the phospho-ethanolamine (PE) linker, a plausible transition from GLYCAM06 to ffSB12 can be constructed from available force field parameters, but with specifically adapted partial charges. Our simulation results with GPI-GFP immersed in DMPC and POPC bilayers shows that the glycan core of the GPI flops down onto the region of lipid head groups, bringing the three biomolecular species into close proximity. The general behavior of the embedded anchor in a rough, in a similar way as its backbone, can be understood in terms of elementary molecular mechanics, but it must be expected to be influenced by the balance of protein-glycan and protein-lipid interactions. This observation raises a number of important questions about force field development in general; in particular, the compatibility of non-bonded interactions between different biomolecular species

Modeling GPI-anchors and GPI-anchored proteins: three disparate biomolecular species in close proximity

2019 Spring National Meeting

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