Dennison Sarah R, Mura Manuela, Harris Frederick, Morton Leslie H G, Zvelindovsky Andrei, Phoenix David A
School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK; School of Applied Science, London South Bank University, 103 Borough Road, London SE1 0AA, UK.
School of Computing Engineering and Physical Science, University of Central Lancashire, Preston PR1 2HE, UK.
Biochim Biophys Acta. 2015 May;1848(5):1111-8. doi: 10.1016/j.bbamem.2015.01.014. Epub 2015 Jan 30.
Maximin H5 is an anionic antimicrobial peptide from amphibians, which carries a C-terminal amide moiety, and was found to be moderately haemolytic (20%). The α-helicity of the peptide was 42% in the presence of lipid mimics of erythrocyte membranes and was found able to penetrate (10.8 mN m(-1)) and lyse these model membranes (64 %). In contrast, the deaminated peptide exhibited lower levels of haemolysis (12%) and α-helicity (16%) along with a reduced ability to penetrate (7.8 m Nm(-1)) and lyse (55%) lipid mimics of erythrocyte membranes. Taken with molecular dynamic simulations and theoretical analysis, these data suggest that native maximin H5 primarily exerts its haemolytic action via the formation of an oblique orientated α-helical structure and tilted membrane insertion. However, the C-terminal deamination of maximin H5 induces a loss of tilted α-helical structure, which abolishes the ability of the peptide's N-terminal and C-terminal regions to H-bond and leads to a loss in haemolytic ability. Taken in combination, these observations strongly suggest that the C-terminal amide moiety carried by maximin H5 is required to stabilise the adoption of membrane interactive tilted structure by the peptide. Consistent with previous reports, these data show that the efficacy of interaction and specificity of maximin H5 for membranes can be attenuated by sequence modification and may assist in the development of variants of the peptide with the potential to serve as anti-infectives.
最大防御素H5是一种来自两栖动物的阴离子抗菌肽，其携带C端酰胺基团，被发现具有中等程度的溶血活性（20%）。在存在红细胞膜脂质模拟物的情况下，该肽的α-螺旋度为42%，并且能够穿透（10.8 mN m⁻¹）并裂解这些模型膜（64%）。相比之下，脱氨肽表现出较低水平的溶血活性（12%）和α-螺旋度（16%），同时穿透（7.8 m Nm⁻¹）和裂解（55%）红细胞膜脂质模拟物的能力也降低。结合分子动力学模拟和理论分析，这些数据表明天然的最大防御素H5主要通过形成倾斜定向的α-螺旋结构和倾斜的膜插入来发挥其溶血作用。然而，最大防御素H5的C端脱氨导致倾斜的α-螺旋结构丧失，这消除了该肽的N端和C端区域形成氢键的能力，并导致溶血能力丧失。综合来看，这些观察结果强烈表明，最大防御素H5携带的C端酰胺基团是该肽稳定采用膜相互作用倾斜结构所必需的。与先前的报道一致，这些数据表明，最大防御素H5与膜相互作用的效率和特异性可通过序列修饰而减弱，这可能有助于开发具有抗感染潜力的该肽变体。
