Graduate School of Medicine and Pharmaceutical Sciences , University of Toyama , 2630 Sugitani , Toyama 930-0194 , Japan.
Institute of Science and Engineering , Kanazawa University , Kakuma , Kanazawa , Ishikawa 920-1192 , Japan.
J Phys Chem B. 2018 Apr 19;122(15):4318-4324. doi: 10.1021/acs.jpcb.8b00298. Epub 2018 Apr 5.
Peptide-induced phospholipid flip-flop (scrambling) was evaluated using transmembrane model peptides in which the central residue was substituted with various amino acid residues (sequence: Ac-GKK(LA) XW(LA) LKKA-CONH). Peptides with a strongly hydrophilic residue (X = Q, N, or H) had higher scramblase activity than that of other peptides, and the activity was also dependent on the length of the peptides. Peptides with a hydrophobic stretch of 17 residues showed high flip-promotion propensity, whereas those of 21 and 25 residues did not, suggesting that membrane thinning under negative mismatch conditions promotes the flipping. Interestingly, a hydrophobic stretch of 19 residues intensively promoted phospholipid scrambling and membrane leakage. The distinctive characteristics of the peptide were ascribed by long-term molecular dynamics simulation to the arrangement of central glutamine and terminal four lysine residues on the same side of the helix. The combination of simulated and experimental data enables understanding of the mechanisms by which transmembrane helices, and ultimately unidentified scramblases in biomembranes, cause lipid scrambling.
肽诱导的磷脂翻转（翻转）是使用其中中央残基被各种氨基酸残基取代的跨膜模型肽来评估的（序列：Ac-GKK（LA）XW（LA）LKKA-CONH）。具有强亲水性残基（X = Q、N 或 H）的肽具有比其他肽更高的翻转酶活性，并且该活性也取决于肽的长度。具有 17 个残基的疏水伸展的肽显示出高的翻转促进倾向，而具有 21 个和 25 个残基的肽则没有，这表明在负不匹配条件下膜变薄促进了翻转。有趣的是，19 个残基的疏水伸展强烈促进了磷脂的翻转和膜的渗漏。通过长期分子动力学模拟，肽的独特特征归因于中心谷氨酰胺和末端四个赖氨酸残基在螺旋的同一侧的排列。模拟和实验数据的结合使我们能够理解跨膜螺旋，以及最终在生物膜中未鉴定的翻转酶，引起脂质翻转的机制。
