Ozdirekcan Suat, Etchebest Catherine, Killian J Antoinette, Fuchs Patrick F J
Department of Chemical Biology and Organic Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
J Am Chem Soc. 2007 Dec 12;129(49):15174-81. doi: 10.1021/ja073784q. Epub 2007 Nov 15.
The orientation of the transmembrane peptide WALP23 under small hydrophobic mismatch has been assessed through long-time-scale molecular dynamics simulations of hundreds of nanoseconds. Each simulation gives systematically large tilt angles (>30 degrees). In addition, the peptide visits various azimuthal rotations that mostly depend on the initial conditions and converge very slowly. In contrast, small tilt angles as well as a well-defined azimuthal rotation were suggested by recent solid-state 2H NMR studies on the same system. To optimally compare our simulations with NMR data, we concatenated the different trajectories in order to increase the sampling. The agreement with 2H NMR quadrupolar splittings is spectacularly better when these latter are back-calculated from the concatenated trajectory than from any individual simulation. From these ensembled-average quadrupolar splittings, we then applied the GALA method as described by Strandberg et al. (Biophys J. 2004, 86, 3709-3721), which basically derives the peptide orientation (tilt and azimuth) from the splittings. We find small tilt angles (6.5 degrees), whereas the real observed tilt in the concatenated trajectory presents a higher value (33.5 degrees). We thus propose that the small tilt angles estimated by the GALA method are the result of averaging effects, provided that the peptide visits many states of different azimuthal rotations. We discuss how to improve the method and suggest some other experiments to confirm this hypothesis. This work also highlights the need to run several and rather long trajectories in order to predict the peptide orientation from computer simulations.
通过数百纳秒的长时间尺度分子动力学模拟，评估了跨膜肽WALP23在小疏水错配情况下的取向。每次模拟都系统地给出了较大的倾斜角（>30度）。此外，该肽经历了各种方位旋转，这些旋转大多取决于初始条件，并且收敛非常缓慢。相比之下，最近对同一系统的固态2H NMR研究表明倾斜角较小且方位旋转明确。为了将我们的模拟与NMR数据进行最佳比较，我们连接了不同的轨迹以增加采样。当从连接轨迹而不是任何单个模拟中反算2H NMR四极分裂时，与实验数据的一致性显著提高。然后，根据Strandberg等人（《生物物理杂志》，2004年，86卷，3709 - 3721页）所述的方法，我们应用GALA方法，该方法基本上从分裂中得出肽的取向（倾斜和方位）。我们得到的倾斜角较小（6.5度），而在连接轨迹中实际观察到的倾斜角更高（33.5度）。因此，我们认为，假设该肽经历了许多不同方位旋转的状态，GALA方法估计的小倾斜角是平均效应的结果。我们讨论了如何改进该方法，并提出了一些其他实验来证实这一假设。这项工作还强调了为了从计算机模拟中预测肽的取向，需要运行多个且相当长的轨迹。
