Translocation of Antimicrobial Peptides across Model Membranes : The Role of Peptide Chain Length

Summary, in English

Cushioned lipid bilayers are structures consisting of a lipid bilayer supported on a solid substrate with an intervening layer of soft material. They offer possibilities for studying the behavior and interactions of biological membranes more accurately under physiological conditions. In this work, we continue our studies of cushion formation induced by histatin 5 (²⁴Hst5), focusing on the effect of the length of the peptide chain. ²⁴Hst5 is a short, positively charged, intrinsically disordered saliva peptide, and here, both a shorter (¹⁴Hst5) and a longer (⁴⁸Hst5) peptide variant were evaluated. Experimental surface active techniques were combined with coarse-grained Monte Carlo simulations to obtain information about these peptides. Results show that at 10 mM NaCl, both the shorter and the longer peptide variants behave like ²⁴Hst5 and a cushion below the bilayer is formed. At 150 mM NaCl, however, no interaction is observed for ²⁴Hst5. On the contrary, a cushion is formed both in the case of ¹⁴Hst5 and ⁴⁸Hst5, and in the latter, an additional thick, diffuse, and highly hydrated layer of peptide and lipid molecules is formed, on top of the bilayer. Similar trends were observed from the simulations, which allowed us to hypothesize that positively charged patches of the amino acids lysine and arginine in all three peptides are essential for them to interact with and translocate over the bilayer. We therefore hypothesize that electrostatic interactions are important for the interaction between the solid-supported lipid bilayers and the peptide depending on the linear charge density through the primary sequence and the positively charged patches in the sequence. The understanding of how, why, and when the cushion is formed opens up the possibility for this system to be used in the research and development of new drugs and pharmaceuticals.

• Author: Amanda E. Skog; Nicolò Paracini; Yuri Gerelli; Marie Skepö
• Department/s: Computational Chemistry; LUNARC, Centre for Scientific and Technical Computing at Lund University; Department of Chemistry; LTH Profile Area: Nanoscience and Semiconductor Technology; NanoLund: Centre for Nanoscience; eSSENCE: The e-Science Collaboration
• Publishing year: 2024-08
• Language: English
• Pages: 4082-4097
• Publication/Series: Molecular Pharmaceutics
• Volume: 21
• Issue: 8
• Links: http://dx.doi.org/10.1021/acs.molpharmaceut.4c00450
• Document type: Journal article
• Publisher: The American Chemical Society (ACS)
• Topic: Physical Chemistry (including Surface- and Colloid Chemistry); Theoretical Chemistry (including Computational Chemistry)
• Keywords: antifungal; antimicrobial; cushion formation; histatin 5; lipid bilayers; model membrane; peptide; saliva; solid-supported lipid bilayers
• Status: Published
• ISBN/ISSN/Other: ISSN: 1543-8384