Bernèche S, Nina M, Roux B
Membrane Transport Research Group (GRTM), Department of Physics, Université de Montréal, C.P. 6128, succ. Centre-Ville, Canada H3C 3J7.
Biophys J. 1998 Oct;75(4):1603-18. doi: 10.1016/S0006-3495(98)77604-0.
Molecular dynamics trajectories of melittin in an explicit dimyristoyl phosphatidylcholine (DMPC) bilayer are generated to study the details of lipid-protein interactions at the microscopic level. Melittin, a small amphipathic peptide found in bee venom, is known to have a pronounced effect on the lysis of membranes. The peptide is initially set parallel to the membrane-solution interfacial region in an alpha-helical conformation with unprotonated N-terminus. Solid-state nuclear magnetic resonance (NMR) and polarized attenuated total internal reflectance Fourier transform infrared (PATIR-FTIR) properties of melittin are calculated from the trajectory to characterize the orientation of the peptide relative to the bilayer. The residue Lys7 located in the hydrophobic moiety of the helix and residues Lys23, Arg24, Gln25, and Gln26 at the C-terminus hydrophilic form hydrogen bonds with water molecules and with the ester carbonyl groups of the lipids, suggesting their important contribution to the stability of the helix in the bilayer. Lipid acyl chains are closely packed around melittin, contributing to the stable association with the membrane. Calculated density profiles and order parameters of the lipid acyl chains averaged over the molecular dynamics trajectory indicate that melittin has effects on both layers of the membrane. The presence of melittin in the upper layer causes a local thinning of the bilayer that favors the penetration of water through the lower layer. The energetic factors involved in the association of melittin at the membrane surface are characterized using an implicit mean-field model in which the membrane and the surrounding solvent are represented as structureless continuum dielectric material. The results obtained by solving the Poisson-Bolztmann equation numerically are in qualitative agreement with the detailed dynamics. The influence of the protonation state of the N-terminus of melittin is examined. After 600 ps, the N-terminus of melittin is protonated and the trajectory is continued for 400 ps, which leads to an important penetration of water molecules into the bilayer. These observations provide insights into how melittin interacts with membranes and the mechanism by which it enhances their lysis.
生成了蜂毒肽在明确的二肉豆蔻酰磷脂酰胆碱（DMPC）双层中的分子动力学轨迹，以在微观层面研究脂质 - 蛋白质相互作用的细节。蜂毒肽是一种存在于蜂毒中的小型两亲性肽，已知对膜的裂解有显著影响。该肽最初以α - 螺旋构象平行于膜 - 溶液界面区域设置，其N端未质子化。根据轨迹计算了蜂毒肽的固态核磁共振（NMR）和偏振衰减全内反射傅里叶变换红外（PATIR - FTIR）特性，以表征该肽相对于双层的取向。位于螺旋疏水部分的残基Lys7以及C端亲水区的残基Lys23、Arg24、Gln25和Gln26与水分子和脂质的酯羰基形成氢键，表明它们对双层中螺旋稳定性的重要贡献。脂质酰基链紧密堆积在蜂毒肽周围，有助于与膜的稳定结合。在分子动力学轨迹上平均计算得到的脂质酰基链的密度分布和序参数表明，蜂毒肽对膜的两层都有影响。上层中蜂毒肽的存在导致双层局部变薄，有利于水通过下层渗透。使用隐式平均场模型表征了蜂毒肽在膜表面结合所涉及的能量因素，其中膜和周围溶剂被表示为无结构的连续介质电介质材料。通过数值求解泊松 - 玻尔兹曼方程获得的结果与详细动力学在定性上一致。研究了蜂毒肽N端质子化状态的影响。600皮秒后，蜂毒肽的N端质子化，并将轨迹继续400皮秒，这导致水分子大量渗透到双层中。这些观察结果为蜂毒肽如何与膜相互作用以及它增强膜裂解的机制提供了见解。
