Eosinophil Major Basic Protein (MBP) is a highly cationic protein with known antimicrobial effects that plays essential roles in host defense, inflammation, and tissue injury. A recent study by Dr. Daniel Butler identified MBP as a potent regulator of inflammatory macrophage activation and bacterial clearance during persistent Salmonella infection, revealing an unexpected role in granuloma biology and innate immunity (1). Despite its biological importance, the molecular mechanisms governing MBP recognition of cellular membranes and extracellular glycocalyx components remain unknown. In particular, how negatively charged membrane lipids and cell-surface heparan sulfate proteoglycans cooperate to regulate MBP recruitment, membrane binding, and subsequent cytotoxic activity has not been explored at molecular resolution. This project will employ multiscale molecular dynamics (MD) simulations to define the molecular basis of MBP interactions with anionic membrane lipids and heparan sulfate proteoglycans, two complementary molecular interfaces governing protein localization, orientation, membrane remodeling, and biological function. Atomistic simulations will characterize residue-specific interactions, binding energetics, and membrane insertion pathways, while coarse-grained simulations will extend these studies to biologically relevant spatial and temporal scales to investigate lipid clustering, membrane deformation, and protein-induced membrane remodeling. Together, these approaches will establish how membrane phospholipids and sulfated glycans cooperatively regulate MBP function at the cell surface. The project brings together the complementary expertise of Dr. Arunima Chaudhuri (Lund University), Dr. Daniel Arve Butler (Lund University), and Dr. Xavier Prasanna (University of Helsinki and University College Dublin). Dr. Chaudhuri has extensive expertise in membrane biology, protein–lipid interactions, and translational membrane research, integrating experimental membrane biophysics, advanced imaging, multiscale molecular simulations, and AlphaFold-based structural modelling to investigate membrane interactions, protein–protein recognition, and membrane remodeling. Her work has established molecular mechanisms underlying membrane-active proteins in cancer and host–pathogen biology through integrated computational and experimental studies published (2–4). Dr. Butler provides the immunological framework of the project through his discovery of MBP-mediated host protection(1), while Dr. Prasanna contributes internationally recognized expertise in multiscale molecular dynamics simulations and membrane biophysics, including pioneering work in PLOS Biology on lipid–protein interactions and membrane organization (5). The requested NAISS computational resources will enable long-timescale atomistic and coarse-grained simulations that are beyond conventional laboratory computing capabilities. These simulations will provide molecular insight into MBP recognition of membranes and the glycocalyx, identify structural determinants governing membrane disruption and immune function, and generate experimentally testable hypotheses. More broadly, this work will establish a mechanistic framework for understanding how cationic immune proteins interact with biological membranes and glycocalyx components, with implications for infectious diseases, eosinophilic disorders, inflammatory pathology, and the development of novel host-directed therapeutics. References 1. Butler DA et al. Nat Microbiol. 10, 3176–3190 (2025). 2. Chaudhuri A, Prasanna X, et al. Sci Rep. 6, 35015 (2016). 3. Sabari S, Chinchankar S, Ambite I...Chaudhuri A, Life Sci Alliance. 8, e202403114 (2025). 4. Chaudhuri A et al. Mol Ther. Accepted (2026). 5. Prasanna X, Salo VT, Li S et al. PLoS Biol. 19, e3000998 (2021).