Interaction and dynamics of chemokine receptor CXCR4 binding with CXCL12 and hBD-3

Chemokine receptor CXCR4 is involved in diverse diseases. A comparative study was conducted on CXCR4 embedded in a POPC lipid bilayer binding with CXCL12 in full and truncated forms, hBD-3 in wildtype, analog, and mutant forms based on in total 63 µs all-atom MD simulations. The initial binding structures of CXCR4 with ligands were predicted using HADDOCK docking or random-seed method, then μs-long simulations were performed to refine the structures. CXCR4&ligand binding structures predicted agree with available literature data. Both kinds of ligands bind stably to the N-terminus, extracellular loop 2 (ECL2), and ECL3 regions of CXCR4; the C2-C3 (K32-R38) region and occasionally the head of hBD-3 bind stably with CXCR4. hBD-3 analogs with Cys11-Cys40 disulfide bond can activate CXCR4 based on the Helix3-Helix6 distance calculation, but not other analogs or mutant. The results provide insight into understanding the dynamics and activation mechanism of CXCR4 receptor binding with different ligands.