(413a) Molecular Dynamics Simulation on Human ? Defensin Type 3 Binding with the CXCR4 Receptor

The chemokine receptor CXCR4 is a membrane-bound G-protein coupled receptor (GPCR) involved with chemotaxis in lymphocytes. Because CXCR4 is involved in inflammatory diseases, cancers, and in the replication of HIV-1, it has become a target of interest for therapeutic control. CXCR4 is activated by its only natural ligand CXCL12, but it also can bind with other proteins such as human β defensin type 3 (hBD-3), which has shown to act as an antagonist. HBD-3 is a cysteine-rich cationic peptide belonging to the human innate immune system, and is mainly secreted from human epithelial tissues and mucosa. It has a broad spectrum of bactericidal abilities, but also modulates adaptive immune response by interacting with chemokine receptors including CCR2, CCR6, and CXCR4. HBD-3 has three disulfide bonds that can break under reducing conditions, and the disulfide bonding status of hBD-3 has been shown to influence its chemotactic activity. In order to understand the structure and dynamics of CXCR4 binding with CXCL12 and hBD-3, all-atom molecular dynamics simulations using NAMD and ANTON programs have been performed on CXCL12, hBD-3 wildtype, and hBD-3 analogs interacting with the CXCR4 receptor embedded in a lipid bilayer. The exact binding structure of hBD-3 with CXCR4 is currently unknown, and the dynamics of CXCR4 activity is poorly understood. This work elucidates the molecular detail of hBD-3’s binding structure with CXCR4, showing results that can agree with experimental work. The conformational dynamics of CXCR4 under various conditions was also explored.