Binding free energy calculation of human beta defensin 3 with negatively charged lipid bilayer using free energy perturbation method.

Human β defensin type 3 (hBD-3) is a cationic peptide having strong antimicrobial activities even at high salt concentrations. The conserved sequence is believed to contribute to its unique antibacterial activities. To design novel drugs based on hBD-3, predicting the binding free energy contribution of each residue on hBD-3 with bacterial membrane is important. Firstly, the stable binding structure of hBD-3 dimer in analog form bound on POPG lipid bilayer was predicted using NAMD simulations, which was confirmed by RMSD, buried surface area, hydrogen bonds, distance map, and insertion depth map calculations. Then, free energy perturbation (FEP) method was applied to calculate the binding free energy of each residue by mutating it into Alanine. It was found that the positively charged residues on the tail region of hBD-3 contribute significantly to its binding with membrane. The result emphasized the importance of electrostatic interactions to hBD-3's binding with bacterial membrane.
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