Kessel Amit, Shental-Bechor Dalit, Haliloglu Turkan, Ben-Tal Nir
Department of Biochemistry, George S Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel.
Biophys J. 2003 Dec;85(6):3431-44. doi: 10.1016/S0006-3495(03)74765-1.
We introduce here a novel Monte Carlo simulation method for studying the interactions of hydrophobic peptides with lipid membranes. Each of the peptide's amino acids is represented as two interaction sites: one corresponding to the backbone alpha-carbon and the other to the side chain, with the membrane represented as a hydrophobic profile. Peptide conformations and locations in the membrane and changes in the membrane width are sampled using the Metropolis criterion, taking into account the underlying energetics. Using this method we investigate the interactions between the hydrophobic peptide M2delta and a model membrane. The simulations show that starting from an extended conformation in the aqueous phase, the peptide first adsorbs onto the membrane surface, while acquiring an ordered helical structure. This is followed by formation of a helical-hairpin and insertion into the membrane. The observed path is in agreement with contemporary understanding of peptide insertion into biological membranes. Two stable orientations of membrane-associated M2delta were obtained: transmembrane (TM) and surface, and the value of the water-to-membrane transfer free energy of each of them is in agreement with calculations and measurements on similar cases. M2delta is most stable in the TM orientation, where it assumes a helical conformation with a tilt of 14 degrees between the helix principal axis and the membrane normal. The peptide conformation agrees well with the experimental data; average root-mean-square deviations of 2.1 A compared to nuclear magnetic resonance structures obtained in detergent micelles and supported lipid bilayers. The average orientation of the peptide in the membrane in the most stable configurations reported here, and in particular the value of the tilt angle, are in excellent agreement with the ones calculated using the continuum-solvent model and the ones observed in the nuclear magnetic resonance studies. This suggests that the method may be used to predict the three-dimensional structure of TM peptides.
我们在此介绍一种新型的蒙特卡罗模拟方法，用于研究疏水性肽与脂质膜的相互作用。肽的每个氨基酸都由两个相互作用位点表示：一个对应于主链α-碳，另一个对应于侧链，而膜则由疏水轮廓表示。使用 metropolis 准则对肽在膜中的构象、位置以及膜宽度的变化进行采样，同时考虑潜在的能量学。利用该方法，我们研究了疏水性肽 M2delta 与模型膜之间的相互作用。模拟结果表明，肽从水相中的伸展构象开始，首先吸附到膜表面，同时获得有序的螺旋结构。随后形成螺旋发夹结构并插入膜中。观察到的路径与当前对肽插入生物膜的理解一致。获得了与膜相关的 M2delta 的两种稳定取向：跨膜（TM）和表面取向，并且它们各自的水-膜转移自由能值与类似情况下的计算和测量结果一致。M2delta 在 TM 取向中最稳定，在该取向中它呈现出螺旋构象，螺旋主轴与膜法线之间的倾斜角度为 14 度。肽的构象与实验数据吻合良好；与在去污剂胶束和支持的脂质双层中获得的核磁共振结构相比，平均均方根偏差为 2.1 Å。此处报道的最稳定构型中肽在膜中的平均取向，特别是倾斜角的值，与使用连续介质溶剂模型计算的值以及在核磁共振研究中观察到的值非常一致。这表明该方法可用于预测跨膜肽的三维结构。
