The main goal of our modeling studies was to explain, at the molecular level, why in some cases, L/D isomerization of a few residues in previously designed cyclic AMPs can significantly improve the pharmacological profile of the peptides by reducing their hemolytic activity without changing antimicrobial properties. We utilized all-atom MD simulations of the peptides, followed by analyses of their structural dynamics and hydrophobic properties, to perform a comparative structure-activity analysis among the previously reported parent peptides and newly designed macrocyclic peptides containing varying numbers of D-amino acids.