Exploring the Interaction of RBD with Human β Defensin Type 2 Point Mutants: Insights from Molecular Dynamics Simulations.

The global health crisis triggered by the SARS-CoV-2 virus has highlighted the urgent need for effective treatments. As existing drugs are not specifically targeted at this virus, there is a growing interest in exploring natural antimicrobial peptides such as defensin as potential therapeutic options. Human β defensin type 2 (hBD-2), which is a cationic cysteine-rich peptide, serves as the initial barrier against bacterial and fungal invaders in mammals. It can bind with Spike-RBD and occupy the same site as the ACE2 receptor, thereby hindering viral entry into cells expressing ACE2. To explore the effect of different point mutations on the binding of hBD-2 with RBD, the binding dynamics and interactions between hBD-2 point mutants with RBD were studied and compared with that of RBD&hBD-2 wild-type complex. In total, 247 hBD-2 point mutants were built with the mutation sites at the binding region of hBD-2 (RES18-30) with the RBD of CoV-2. All-atom molecular dynamics simulations were carried out on RBD binding with hBD-2 point mutants. Analysis based on root-mean-square deviation (RMSD), hydrogen bonds analysis, and binding free energy using the MM/PBSA method revealed that many point mutants of hBD-2 exhibit weaker binding with RBD compared to the wild type; however, a subset of mutants, including C20I, C20K, R22W, R23H, R23L, Y24L, K25F, K25H, G28Y, T29R, and C30K, displayed enhanced binding with RBD. The findings can offer insights designing hBD-2-based novel drugs to combat SARS-CoV-2 in the long term.