Fine‐Tuning Gramicidin S: How <i>δ</i>‐Phenylproline Affects Turns and Interaction with Membrane

The incorporation of a phenyl ring at the 5‐position of proline markedly influences the conformation and membrane interactions of gramicidin S. Herein, the structural and biophysical consequences of introducing cis ‐5‐phenyl‐L‐proline into gramicidin S are computationally investigated, with a particular focus on its conformational behavior and lipid bilayer interactions. Using a homochiral model dipeptide, it is shown that cis ‐5‐phenyl‐L‐proline promotes the formation of a double γ ‐turn, significantly altering the peptide's folding characteristics. This conformational bias is transferred to the modified gramicidin S scaffold, where it perturbs the native amphipathic balance and results in less favorable membrane interactions. These findings underscore the pivotal role of proline‐derived modifications in shaping the structural and functional properties of cyclic peptides and offer valuable insights into how targeted substitutions can modulate peptide–membrane interactions.