Rangubpit Warin, Distaffen Hannah E, Nilsson Bradley L, Dias Cristiano L
Department of Physics, New Jersey Institute of Technology, Newark, NJ 07102-1982, USA.
Department of Chemistry, University of Rochester, Rochester, NY 14627-0216, USA.
Biomolecules. 2025 Jul 7;15(7):973. doi: 10.3390/biom15070973.
Peptide-induced disruption of lipid membranes is central to both amyloid diseases and the activity of antimicrobial peptides. Here, we combine all-atom molecular dynamics simulations with biophysical experiments to investigate how four amphipathic peptides interact with lipid bilayers. All peptides adsorb on the membrane surface. Peptide M01 [Ac-(FKFE)-NH] self-assembles into β-sheet nanofibrils that span both leaflets of the membrane, creating water-permeable channels. The other three peptides adopt α-helical structures at the water-lipid interface. Peptide M02 [Ac-FFKKFFEE-NH], a sequence isomer of M01, does not form β-sheet aggregates and is too short to span the bilayer, resulting in no observable water permeation across the membrane. Peptides M03 and M04 are α-helical isomers long enough to span the bilayer, with a polar face that allows the penetration of water deep inside the membrane. For the M03 peptide [Ac-(FFKKFFEE)-NH], insertion into the bilayer starts with the nonpolar N-terminal amino acids penetrating the hydrophobic core of the bilayer, while electrostatic interactions hold negative residues at the C-terminus on the membrane surface. The M04 peptide, [Ac-FFKKFFEEFKKFFEEF-NH], is made by relocating a single nonpolar residue from the central region of M03 to the C-terminus. This nonpolar residue becomes unfavorably exposed to the solvent upon insertion of the N-terminal region of the peptide into the membrane. Consequently, higher concentrations of M04 peptides are required to induce water permeation compared to M03. Overall, our comparative analysis reveals how subtle rearrangements of polar and nonpolar residues modulate peptide-induced water permeation. This provides mechanistic insights relevant to amyloid pathology and antimicrobial peptide design.
肽诱导的脂质膜破坏在淀粉样疾病和抗菌肽的活性中都起着核心作用。在这里，我们将全原子分子动力学模拟与生物物理实验相结合，以研究四种两亲性肽如何与脂质双层相互作用。所有肽都吸附在膜表面。肽M01 [Ac-(FKFE)-NH] 自组装成跨越膜的两个小叶的β-折叠纳米纤维，形成水可渗透的通道。其他三种肽在水-脂质界面采用α-螺旋结构。肽M02 [Ac-FFKKFFEE-NH] 是M01的序列异构体，不形成β-折叠聚集体且太短而无法跨越双层，导致没有可观察到的水透过膜。肽M03和M04是足够长以跨越双层的α-螺旋异构体，其极性面允许水深入膜内部渗透。对于M03肽 [Ac-(FFKKFFEE)-NH]，插入双层开始于非极性N端氨基酸穿透双层的疏水核心，而静电相互作用将C端的负电荷残基保持在膜表面。M04肽 [Ac-FFKKFFEEFKKFFEEF-NH] 是通过将一个非极性残基从M03的中心区域重新定位到C端而制成的。当肽的N端区域插入膜中时，这个非极性残基不利地暴露于溶剂中。因此，与M03相比，需要更高浓度的M04肽来诱导水渗透。总体而言，我们的比较分析揭示了极性和非极性残基的细微重排如何调节肽诱导的水渗透。这提供了与淀粉样病理和抗菌肽设计相关的机制见解。
