Molecular Basis of Polyethylene Glycol Immunogenicity and the Biocompatibility of Polyglycerol: An Integrated Study from IgE Atomic Dynamics to Systemic Inflammation

Our results provide the first integrated explanation for PEG immunogenicity, ranging from the molecular level (IgE conformational change) to the systemic response (mast cell activation, cytokine release, lipid consumption). The discovery that PEG induces an allergenic IgE conformation—mimicking the receptor-bound state (2WQR)—while PGL preserves the native conformation (2Y7Q), establishes a rational basis for replacing PEG with PGL in pharmaceutical formulations. This finding is supported by PGL’s more favorable binding energies and the stabilizing hydrogen-bond network formed with FcεRI interface residues (Gln128, Ser156, Asp159). The in silico model of mast cell activation, calibrated with real-world clinical data, not only reproduces the observed dynamics but also reveals mechanisms not apparent in the raw data: The role of autotaxin and LPA in response amplification; The importance of cytokine clearance in the resolution of the condition; The possibility that LPA-mediated positive feedback explains recurrences; The sensitivity analysis identifies IL-6 and histamine as priority therapeutic targets, consistent with the clinical use of tocilizumab (anti-IL-6R) and antihistamines in the patient studied.