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Arg and Trp are highly prevalent amino acids in natural and synthetic efficient CPP sequences. In particular, Trp is essential and cannot be substituted by other hydrophobic or aromatic amino acids. The aim of the present study is to decipher the role of Trp in synthetic Arg\/Trp CPP sequences. To do so, a small peptide library in which this residue was substituted by other natural or nonnatural amino acids was designed. Internalization of these peptides in cells was evaluated, and it appeared that combining aromaticity and hydrophobicity in the presence of Arg residues leads to enhanced internalization. The study of the interaction of these peptides with model lipid membranes revealed that the modulation of hydrophobicity promoted insertion in bilayers but had little impact on the binding affinity. On the other hand, more hydrophobic substitutes of Trp led to more favorable binding enthalpies to heparin. With density functional theory (DFT) analysis, we suggest that ion\u2010pair\u00b7\u00b7\u00b7\u03c0 interactions between the aromatic ring and the ion pair formed by the positively charged Arg and the negatively charged cell surface groups can be established and could be at the origin of the unique internalization properties of Trp\u2010containing Arg\u2010rich CPPs.<\/jats:p>","DOI":"10.1002\/chem.202501138","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T06:05:13Z","timestamp":1750399513000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Hydrophobic and Polarized Aromatic Residues Promote Internalization of Arg\u2010Rich Cell\u2010Penetrating Peptides through Ionpair\u2010\u03c0 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