From Membrane Mechanics to Immune Regulation: Molecular Simulations of Lipid-Protein Interplay

Processes in cellular membranes are of utmost importance for all forms of life and therefore an ongoing research focus. In this thesis, we address how membrane lipids collectively shape membrane mechanical properties, and how the interaction of membrane-embedded immune receptors contributes to immune signaling. The high spatial and temporal resolution of molecular dynamics (MD) simulations predestines them to study these topics and the underlying mechanisms. The standard setup in MD simulations uses membranes that are connected to their periodic images and thereby suppresses thermal membrane undulations and spontaneous, e.g. protein-induced, membrane curvature. Here, an improved lipid bicelle simulation setup is developed in which the investigated membrane patch is disconnected from its periodic images and can therefore show unbiased undulations and curvature. This study shows that the setup is beneficial for the investigation of protein-induced membrane deformation and asymmetric membranes. It is for example revealed that the cholesterol density of a plasma membrane mimic is increased by 28% in the extracellular leaflet. Being a major component of cellular membranes and necessary for processes of membrane reshaping, it is key to uncover not only the distribution of cholesterol in the bilayer, but also its impact on the structural and elastic properties of membranes. Assisted by the novel bicelle setup, this work studies the non-universal impact of cholesterol on these membrane characteristics for saturated and unsaturated lipids. On the one hand, cholesterol causes membrane thickening and lipid compression for both lipid types. On the other hand, it prefers the compressed leaflet of curved membranes and therefore facilitates bending via local cholesterol redistribution. In unsaturated membranes the latter effect dominates due to increased cholesterol mobility, resulting in an overall softening of the membrane. Regarding immune signaling, immunoglobulin G antibodies fulfill a dual role during immune reactions since they exert both pro- and anti-inflammatory activity. In the treatment of rheumatoid arthritis with intravenous immunoglobulin (IVIg), the pathway for the IVIg mediated inhibition of bone destruction was so far unclear. It was shown experimentally that IVIg stops the maturation of monocytes into osteoclast, that this pathway is dependent on both FcγRIIb and Dectin-1, and that Dectin-1 enhances IVIg binding to FcγRIIb. This thesis uses MD simulations to reveal that the FcγRIIb Dectin-1 interaction is mediated by a transmembrane domain driven specific dimerization resulting in a dimer structure that enhances IVIg binding by keeping the ectodomain of FcγRIIb upright.