Wang Fang, Qin Luoheng, Wong Patrick, Gao Jianmin
Department of Chemistry, Merkert Chemistry Center, Boston College, 2609 Beacon Street, Chestnut Hill, MA, 02467.
Biopolymers. 2013 Nov;100(6):656-61. doi: 10.1002/bip.22268.
Protein-membrane interactions underlie numerous biological processes including folding of ion channels and signal transduction across lipid membranes. A detailed understanding of protein-lipid interactions is critical for designing membrane-active peptides as potential antibiotics, as well. Using gramicidin A (gA) as a model system, we investigated the effects of lysine methylation on peptide folding into transmembrane channels. The results are discussed in terms of the peptides' binding affinity to, translocation across, and structure formation in lipid membranes. The results show that gA mutants with N(ɛ)-trimethylated D-lysines (dMe3 K) are capable of folding into wild type-like channels that are selective for monovalent cations. Surprisingly, N(ɛ)-trimethylation in general reduces the peptide's binding affinity to lipid membranes despite the increased hydrophobicity. Further investigation reveals the critical contribution of the hydrogen bonding potential of lysine side chains to peptide-membrane association, which has previously been underappreciated. Importantly, methylation does give improved therapeutic indices for certain combinations of gA variant and bacterium, indicating that methylation can be an effective strategy to fine tune the performance of peptide antibiotics.
蛋白质 - 膜相互作用是众多生物过程的基础，包括离子通道的折叠和跨脂质膜的信号转导。详细了解蛋白质 - 脂质相互作用对于设计作为潜在抗生素的膜活性肽也至关重要。我们以短杆菌肽A（gA）作为模型系统，研究了赖氨酸甲基化对肽折叠成跨膜通道的影响。从肽与脂质膜的结合亲和力、跨膜转运以及结构形成方面对结果进行了讨论。结果表明，具有N（ɛ）-三甲基化D - 赖氨酸（dMe3 K）的gA突变体能够折叠成对单价阳离子具有选择性的野生型样通道。令人惊讶的是，尽管疏水性增加，但一般来说N（ɛ）-三甲基化会降低肽与脂质膜的结合亲和力。进一步研究揭示了赖氨酸侧链氢键潜力对肽 - 膜缔合的关键贡献，这一点此前未得到充分重视。重要的是，甲基化确实为gA变体和细菌的某些组合提供了更好的治疗指数，表明甲基化可以是微调肽类抗生素性能的有效策略。
