The transient disruption of membranes for the passive permeation of ions or small molecules is a complex process relevant to understanding physiological processes and biotechnology applications. Phenolic compounds are widely studied for their antioxidant and antimicrobial properties, and some of these activities are based on the interactions of the phenolic compound with membranes. Ions are ubiquitous in cells and are known to alter the structure of phospholipid bilayers. Yet, ion-lipid interactions are usually ignored when studying the membrane-altering properties of phenolic compounds. This study aims to assess the role of Ca²⁺ ions on the membrane-disrupting activity of two phenolic acids and to highlight the role of local changes in lipid packing in forming transient defects or pores. Results from tethered bilayer lipid membrane electrical impedance spectroscopy experiments showed that Ca²⁺ significantly reduces membrane disruption by caffeic acid methyl ester and caffeic acid. As phenolic acids are known metal chelators, we used UV-vis and fluorescence spectroscopy to exclude the possibility that Ca²⁺ interferes with membrane disruption by binding to the phenolic compound and subsequently preventing membrane binding. Molecular dynamics simulations showed that Ca²⁺ but not caffeic acid methyl ester or caffeic acid increases lipid packing in POPC bilayers. The combined data confirm that Ca²⁺ reduces the membrane-disrupting activity of the phenolic compounds, and that Ca²⁺-induced changes to lipid packing govern this effect. We discuss our data in the context of ion-induced pores and transient defects and how lipid packing affects membrane disruption by small molecules.

用于离子或小分子被动渗透的膜的瞬时破坏是一个与理解生理过程和生物技术应用相关的复杂过程。酚类化合物因其抗氧化和抗菌特性而被广泛研究，其中一些活性是基于酚类化合物与膜的相互作用。离子在细胞中普遍存在，并且已知可以改变磷脂双层的结构。然而，在研究酚类化合物的膜改变特性时，离子-脂质相互作用通常被忽略。本研究旨在评估 Ca ²⁺离子对两种酚酸膜破坏活性的作用，并强调脂质堆积的局部变化在形成瞬时缺陷或孔中的作用。系链双层脂质膜电阻抗光谱实验的结果表明，Ca ²⁺显着减少咖啡酸甲酯和咖啡酸对膜的破坏。^{由于酚酸是已知的金属螯合剂，我们使用紫外可见分光光度法和荧光光谱来排除 Ca 2+}通过与酚类化合物结合并随后阻止膜结合而干扰膜破坏的可能性。分子动力学模拟表明，Ca ²⁺但咖啡酸甲酯或咖啡酸不会增加 POPC 双层中的脂质堆积。综合数据证实，Ca ²⁺降低了酚类化合物的膜破坏活性，并且 Ca ²⁺诱导的脂质堆积变化控制了这种效应。我们在离子诱导的孔隙和瞬时缺陷以及脂质堆积如何影响小分子的膜破坏的背景下讨论我们的数据。