Shepherd Craig M, Vogel Hans J, Tieleman D Peter
Department of Biological Sciences, University of Calgary, 2500 University Drive N.W., Calgary, AB, Canada T2N 1N4.
Biochem J. 2003 Feb 15;370(Pt 1):233-43. doi: 10.1042/BJ20021255.
Molecular-dynamics simulations covering 30 ns of both a natural and a synthetic antimicrobial peptide in the presence of a zwitterionic lipid bilayer were performed. In both simulations, copies of the peptides were placed in an alpha-helical conformation on either side of the bilayer about 10 A (1 A=0.1 nm) from the interface, with either the hydrophobic or the positively charged face of the helix directed toward the bilayer surface. The degree of peptide-lipid interaction was dependent on the starting configuration: surface binding and subsequent penetration of the bilayer was observed for the hydrophobically oriented peptides, while the charge-oriented peptides demonstrated at most partial surface binding. Aromatic residues near the N-termini of the peptides appear to play an important role in driving peptide-lipid interactions. A correlation between the extent of peptide-lipid interactions and helical stability was observed in the simulations. Insertion of the peptides into the bilayer caused a dramatic increase in the lateral area per lipid and decrease in the bilayer thickness, resulting in substantial disordering of the lipid chains. Results from the simulations are consistent with early stages of proposed mechanisms for the lytic activity of antimicrobial peptides. In addition to these 'free' simulations, 25 ns simulations were carried out with the peptides constrained at three different distances relative to the bilayer interface. The constraint forces are in agreement with the extent of peptide-bilayer insertion observed in the free simulations.
在两性离子脂质双层存在的情况下，对一种天然抗菌肽和一种合成抗菌肽进行了长达30纳秒的分子动力学模拟。在这两种模拟中，肽的拷贝以α螺旋构象放置在双层两侧，距离界面约10埃（1埃=0.1纳米），螺旋的疏水面或带正电的面朝向双层表面。肽与脂质的相互作用程度取决于起始构型：对于疏水取向的肽，观察到其与表面结合并随后穿透双层，而电荷取向的肽最多表现出部分表面结合。肽N端附近的芳香族残基似乎在驱动肽-脂质相互作用中起重要作用。在模拟中观察到肽-脂质相互作用程度与螺旋稳定性之间的相关性。肽插入双层导致每个脂质的侧向面积显著增加，双层厚度减小，导致脂质链出现大量无序排列。模拟结果与抗菌肽裂解活性的拟议机制的早期阶段一致。除了这些“自由”模拟外，还对肽在相对于双层界面的三个不同距离处进行了约束的25纳秒模拟。约束力与在自由模拟中观察到的肽-双层插入程度一致。
