Fine-Tuning Gramicidin S: How δ-Phenylproline Affects Turns and Interaction with Membrane.

Abstract

The introduction of a phenyl ring at the 5-position of proline significantly impacts the conformation and membrane interactions of Gramicidin S. In this study, we investigate the effects of incorporating cis-5-phenyl-L-proline into Gramicidin S, focusing on its structural behavior and interaction with lipid bilayers. Using a homochiral model dipeptide, we demonstrate that cis-5-phenyl-L-proline induces a double γ-turn, altering the peptide’s folding properties. This conformational bias is then translated into Gramicidin S, where the modified structure disrupts its natural amphipathic balance, leading to unfavorable interactions with membranes. Spectroscopic and biophysical analyses confirm that the modified peptide deviates from the native β-sheet structure, likely reducing its membrane activity. These findings highlight the critical role of proline-derived structural modifications in dictating the bioactivity of cyclic peptides and provide insight into how strategic substitutions can modulate peptide-membrane interactions.