Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea.
J Phys Chem B. 2024 Oct 10;128(40):9756-9771. doi: 10.1021/acs.jpcb.4c03766. Epub 2024 Sep 30.
Research on antimicrobial peptides (AMPs) has been conducted as a solution to overcome antibiotic resistance. In particular, the synergistic effect that appears when two or more AMPs are used in combination has been observed. To find an effective synergistic combination, it is necessary to understand the underlying mechanism. However, a consistent explanation for this phenomenon has not yet been provided due to limitations in experimentally determining or predicting the structure of the heteroaggregates formed by the interactions between different AMPs and the interaction of the aggregate surface with the lipid membrane surface. In this study, we conducted molecular dynamics simulations for two heterogeneous aggregates of melittin-indolicidin and pexiganan-indolicidin to observe their structures in the solution phase and their interactions with the lipid membrane. We aimed to determine how the surfaces of these aggregates interact with the lipid membrane. Due to the different amino acid residue sequence characteristics of melittin and pexiganan, we found that when the two AMPs bind to indolicidin, they form aggregates with completely different structural characteristics. Accordingly, the sequence characteristics of pexiganan, which exhibits a relatively unstable structure compared to melittin in aqueous solution or on lipid membranes, allow for a more stable interaction with the lipid membrane when forming aggregates with indolicidin, effectively inhibiting the integrity of the lipid membranes. We also found that the amino acid residues forming the surface of the AMP aggregate show differential binding strengths to different lipid species forming the lipid membrane, thereby disrupting the membrane in a way that weakens its integrity. Through this, we provided insight into the basic principle of how the synergistic effect of AMPs occurs.
抗菌肽（AMPs）的研究作为克服抗生素耐药性的一种解决方案已经展开。特别是，当两种或更多 AMP 联合使用时，会观察到协同效应。为了找到有效的协同组合，有必要了解其潜在机制。然而，由于在实验中确定或预测不同 AMP 之间相互作用形成的异质聚集体的结构以及聚集体表面与脂质膜表面的相互作用方面存在限制，因此尚未对此现象提供一致的解释。在这项研究中，我们对两种不同的蜂毒素-吲哚西定和佩西加南-吲哚西定的异质聚集体进行了分子动力学模拟，以观察它们在溶液相中的结构及其与脂质膜的相互作用。我们旨在确定这些聚集体的表面如何与脂质膜相互作用。由于蜂毒素和佩西加南的氨基酸残基序列特征不同，我们发现当两种 AMP 与吲哚西定结合时，它们形成具有完全不同结构特征的聚集体。因此，与在水溶液或脂质膜上相比，佩西加南的结构相对不稳定，当与吲哚西定形成聚集体时，其与脂质膜的相互作用更稳定，有效地抑制了脂质膜的完整性。我们还发现，形成 AMP 聚集体表面的氨基酸残基对形成脂质膜的不同脂质种类表现出不同的结合强度，从而以削弱其完整性的方式破坏膜。通过这种方式，我们深入了解了 AMP 协同效应发生的基本原理。
