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Human defensin 5 (HD5) is an antimicrobial peptide (AMP) with a broad-spectrum antimicrobial activity. Hence, it serves as a good candidate in AMP-derived antibiotic design. A substitution of E21 with arginine (E21R) and a second replacement of T7 with arginine (T7E21R) were found to enhance the antibacterial activity where the molecular insights into how these mutations enhance the bacteria-killing activity remains unclear. In this work, Molecular Dynamics (MD) simulations were employed to elucidate the binding mechanisms of both variants (E21R and T7E21R) on bacterial membrane. The dimaeric E21R shares similar adsorption mechanism to wildtype HD5 by using one chain to adhere to the bacterial membrane. In contrast, the more positively charged T7E21R employs both chains to bind to the membrane, resulting in greater membrane-binding ability. Nevertheless, the antibacterial activity of T7E21R is oligomeric state-independent. Both T7E21R monomer and dimer interact strongly with the membrane due to their high positive charges. Nonetheless, such high charges also hinder membrane translocation of the peptide. The positive charge of defensin-based antibiotics needs to be optimal to balance between their membrane-binding ability and their ability to translocate through bacterial membrane. This information serves as a useful guide for designing antimicrobial agents with membrane-disrupting function.

Molecular insights into the adsorption mechanism of E21R and T7E21R human defensin 5 on a bacterial membrane