Glycosylphosphatidylinositols (GPIs) are a class of complex glycolipids abundant on cell surfaces of eukaryotes. They exist either as free species or anchor a protein to the plasma membrane. GPI anchored proteins are known to contribute to a broad variety of cellular processes such as signal transduction, protein trafficking and sorting; free GPIs play an important role in the pathogenesis of many parasites. GPIs possess a conserved glycan core which can be modified and extended by various carbohydrate side chains or phospho-ethanolamine groups. However, except for a few cases a general structure-function relationship for this class of glycolipids does not yet exist. One of the reasons is that in experiments, the mutual interaction and structure of e.g. a GPI anchored protein, possibly depending on its composition, are difficult to characterize unambiguously.<br/>We have therefore developed a dual strategy to study GPIs and GPI anchored proteins with computer simulations. At the atomistic level, we have created a hybrid link to construct GPI anchors from two state-of-the-art AMBER force fields for lipids (Lipid14) and carbohydrates (GLYCAM06), facilitating a straightforward modular buildup of various anchor structures. Our results for various GPI fragments inserted into lipid bilayers suggest that the carbohydrate core prefers to flop down onto a membrane, interacting with the lipid head groups. Attaching green fluorescent protein (GFP) shows that all three species, GPI carbohydrates, the protein and lipid headgroups are in general in close proximity, mutually interacting. Extending the model to study parasitic GPIs such Toxoplasma Gondii and Trypanosoma Congolense revealed the source of antibody specificity by identifying which carbohydrate residue is exposed most to the aqueous subphase.<br/>At a coarse-grained (CG) level we have developed a model in the framework of the MARTINI force field with polarizable waters. We will sketch how the CG model can be used with models of heterogeneous lipid membranes exhibiting ordered and disordered domains to elucidate how GPIs and GPI-anchored proteins distribute across different domains.

Putting force fields to the test: Mutual interaction of aminoacids, lipids, and carbohydrates with GPI-anchored proteins inserted into lipid bilayers and membranes

2019 Fall National Meeting

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