77
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.
