Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery: Bridging Experiments and Computations - September 10-14, 2014, Istanbul, Turkey

Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Poster Session I

24-POS Board 24 In Silico Analysis and Experiments of Potential Anti-Inflammatory Peptides Inhibiting the Binding of Chemokine CXCL8 with Its Receptors CXCR1 and 2 Yi Chung 1 , Shinn-Jong Jiang 2 , Je-Wen Liou 2 , Hao-Jen Hsu 1 . 1 Department of Life Sciences, Tzu Chi University, Hualien City, Taiwan, 2 Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien City, Taiwan. Chemokine CXCL8 secreted by macrophages, endothelial cells, epithelial cells, mast cells and fibroblasts plays a central role in human immune and inflammatory response by binding to and activating its cognate G-protein coupled receptors CXCR1 and CXCR2. Upon binding of CXCL8, CXC receptors undergo conformational changes resulting in downstream signal transduction. The chemokine receptors have been identified as attractive targets for therapeutic intervention in various diseases due to the role of chemokine in immune and inflammatory responses. The purpose of this study was to use molecular docking to determine the potential anti- inflammatory peptides to inhibit CXCL8 binding to its receptors CXCR1 and 2. The docking results showed that monomeric CXCL8 initially binds to CXCR1 and 2 at similar binding sites dominated by electrostatic interactions. The binding complex systems including monomeric and short peptide CXCL8 with CXCR1 and 2 were then embedded into the POPC lipid bilayers for 300 ns MD simulations respectively. The binding free energy (Δ G bind ) calculated by MM/PBSA technique indicated that the Δ G bind of monomeric CXCL8 to CXCR1 is much lower than that of monomeric CXCL8 to CXCR2. On the other hand, the Δ G bind for short peptide of CXCL8 to CXCR1 is also lower than that for monomeric CXCL8 to CXCR1, indicating that the determined potential peptide has a better competitive binding advantage to CXCR1 and 2 than that of monomeric CXCL8. The bio-assay experiments further verified that the synthesized potential peptide can significantly decrease LPS and CXCL8 induced monocyte adhesion to endothelial cells and inhibit monocytic migration induced by inflammation.

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