Complex oligosaccharides often act as to modify the properties of biomolecules in a subtle way, for instance, with regards to solubility or the stability of certain proteins or to provide multivalent receptors on cell surfaces. From the perspective of an engineer one may state that nature uses modifications with carbohydrates, also referred to as glycans, to convey or tune molecular properties <i>a posteriori</i>. The functionalities of glycans range from basic molecular recognition (“key-lock” principle) to rather general or multi-purpose tasks that do not involve simple receptor-ligand complexes. It is in these cases where computational studies with atomistic models are most wanted in order to interpret (or conciliate opposing views on) experimental results – and where they are most unreliable. Here we present previous and recent results from modeling glycosylphosphatidyl-inositol (GPI-) anchors that nicely illustrate this conflict. GPI-anchors may be considered as special types of glycolipids that are post-translationally added to a variety of proteins in order to tie them to the outer leaflet of eukaryotic cell membranes. This anchoring mechanism is thought to be essential to a large number of biological functions. The close proximity of lipids, carbohydrates and amino acids presents the first dilemma to atomistic modeling as no force field parametrization has ever directly been devoted to cover situations of this universality. The second dilemma is related to how the model can make predictions that can actually be tested in experiment, given that any direct connection between structure and function is out of reach. We suggest that the two dilemmas may be alleviated to some extent. For instance, by organizing the simulation study in a hierarchical fashion the flop down model of a GPI anchored protein can be made quite plausible. This and other results are insensitive to reasonable variations in the force field parametrization. A systematic study of variation in the mutual interaction strengths between the different molecular species is most efficient and insightful on the coarse grain level, at which a number of free GPIs and GPI anchored proteins can be studied in heterogeneous membrane patches

Glycosylphosphatidyl-Inositol anchors as an ultimate challenge for the computational modeling of glycans

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.