Data about the effect of minimal structural modifications of membrane interaction of short antimicrobial peptides

Antimicrobial resistance requires the development of new strategies to effectively control bacterial infections. In this work, a series of sixteen short antimicrobial peptide derivatives was synthesized by solid-phase peptide synthesis (SPPS), introducing minimal structural modifications aimed at modulating biological activity and toxicity. The peptides were evaluated for antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa, including both reference and clinical strains, together with cytotoxicity and hemolysis assays. The datasets supporting this evaluation are here reported and demonstrate the efficacy of the synthesized compounds. The applied structural modifications, such as halogenation, bulky alkyl substitutions, and amino acid replacements, were investigated in relation to their impact on peptide–membrane interactions. Molecular dynamics simulations, here reported as dataset, were performed to explore the structural features governing peptide–membrane interactions, highlighting the contribution of amphipathic arrangements and π–π interactions in membrane association.