Molecular Mechanism of the Affinity Interactions between BAFF and Its Peptides by Molecular Simulations

B-cell activating factor (BAFF) belonging to the TNF family, plays an important role in the proliferation and differentiation of B cells which renders it an attractive target for autoimmune diseases. Some peptides have been designed to target BAFF for the treatment of autoimmune diseases. Our previous studies suggested that peptides TA and DX-814 had competitive bioactivities compared to the natural peptide trans-membrane activator and calcium modulator and cyclophilin ligand interactor (TACI) in different binding orientations. In this study, we carried out molecular modeling and dynamics and molecular docking calculations to explore the structural and chemical features responsible for the binding affinities of these peptides. Binding free energy calculations, mutational analyses were also conducted to validate our findings. The result showed that hydrophobic and electrostatic interactions are the dominant forces for binding. DX-814 had a similar binding orientation with BCMA in a conserved hydrophobic pocket and formed electrostatic interaction with conserved arginine residues on the BAFF surface, compared with TA which might interact with a sub-pocket of BAFF in a different orientation. These results provide a thorough understanding of the binding mode between BAFF and its peptide inhibitors at the molecular level and further guide inhibitor design.