Pašalić, Lea; Jakas, Andreja; Čikoš, Ana; Pem, Barbara; Bakarić, Danijela (2026) Deciphering the Influence of Side Chains of Short Cationic Hydrophobic Peptides on Macroscopic and Molecular Properties of Mixed Lipid Bilayers. Journal of Membrane Biology, 259 . ISSN 0022-2631
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Abstract
Cell-penetrating peptides (CPPs) are increasingly used for delivering cargo into cells, but the mechanisms of their membrane crossing remain poorly understood, even for shorter cationic hydrophobic peptides. This study explores how cationic hydrophobic peptides with various combinations of cationic (K and R) and hydrophobic (W and I) amino acids interact with lipid bilayers made of 90% neutral lipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (PC) and 10% anionic lipids (either 1,2-dipalmitoyl-sn-glycero-3-phosphatidylglycerol (PG) or 1,2-dipalmitoyl-sn-glycero-3-phosphoserine (PS)). Specifically, it was found that changing the hydrophobic segment from W to I significantly influences turbidity during the pretransition for the PC/PG mixture. Conversely, in the PC/PS mixture, the interaction with I-peptides causes changes in turbidity during the main phase transition, regardless of whether the cationic segment is R or K. Molecular features analyzed through FTIR spectroscopy revealed significant differences in the vibrations of methylene groups within hydrocarbon chains. In the presence of I-peptides, regardless of whether they are R or K derivatives, a notably higher number of kink conformers were observed compared to W-peptides. Although W-peptides tend to form aggregates due to the insertion of their hydrophobic segments into the lipid bilayer, they appear to maintain the membrane’s integrity and the organization of lipids. In contrast, the branched side chains of the I-segment induce out-of-plane movements in the hydrocarbon chains. As the initial interaction between the peptide and the lipid membrane is crucial for its translocation, these findings provide insights into the molecular events occurring before translocation and emphasize the specifics that make it unique to CPPs.
| Item Type: | Article | ||||||||
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| Additional Information: | This version of the article has been accepted for publication, after peer review and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: http://dx.doi.org/10.1007/s00232-026-00373-8 | ||||||||
| Uncontrolled Keywords: | 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC); 1,2-dipalmitoyl-sn-glycero-3-phosphatidylglycerol (DPPG) and 1,2-dipalmitoyl-sn-glycero-3-phosphoserine (DPPS); Cationic hydrophobic peptides R5W2, K5W2, R5I2, K5I2 ; Spectroscopy (FTIR-ATR and UV-Vis) and calorimetry (DSC); molecular dynamics (MD) | ||||||||
| Subjects: | NATURAL SCIENCES NATURAL SCIENCES > Chemistry NATURAL SCIENCES > Chemistry > Physical Chemistry |
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| Divisions: | Division of Organic Chemistry and Biochemistry NMR Center |
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| Depositing User: | Danijela Bakarić | ||||||||
| Date Deposited: | 18 Mar 2026 10:35 | ||||||||
| URI: | http://fulir.irb.hr/id/eprint/11356 | ||||||||
| DOI: | 10.1007/s00232-026-00373-8 |
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