Department of Computer Science, School of Computing, Tokyo Institute of Technology, W8-76, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8550, Japan.
Middle-Molecule IT-based Drug Discovery Laboratory (MIDL), Tokyo Institute of Technology, RGBT2-A-1C, 3-25-10 Tonomachi, Kawasaki-ku, Kawasaki City, Kanagawa 210-0821, Japan.
J Chem Inf Model. 2021 Jul 26;61(7):3681-3695. doi: 10.1021/acs.jcim.1c00380. Epub 2021 Jul 8.
Membrane permeability is a significant obstacle facing the development of cyclic peptide drugs. However, membrane permeation mechanisms are poorly understood. To investigate common features of permeable (and nonpermeable) designs, it is necessary to reproduce the membrane permeation process of cyclic peptides through the lipid bilayer. We simulated the membrane permeation process of 100 six-residue cyclic peptides across the lipid bilayer based on steered molecular dynamics (MD) and replica-exchange umbrella sampling simulations and predicted membrane permeability using the inhomogeneous solubility-diffusion model and a modified version of it. Furthermore, we confirmed the effectiveness of this protocol by predicting the membrane permeability of 56 eight-residue cyclic peptides with diverse chemical structures, including some confidential designs from a pharmaceutical company. As a result, a reasonable correlation between experimentally assessed and calculated membrane permeability of cyclic peptides was observed for the peptide libraries, except for strongly hydrophobic peptides. Our analysis of the MD trajectory demonstrated that most peptides were stabilized in the boundary region between bulk water and membrane and that for most peptides, the process of crossing the center of the membrane is the main obstacle to membrane permeation. The height of this barrier is well correlated with the electrostatic interaction between the peptide and the surrounding media. The structural and energetic features of the representative peptide at each vertical position within the membrane were also analyzed, revealing that peptides permeate the membrane by changing their orientation and conformation according to the surrounding environment.
膜通透性是环状肽类药物发展面临的重大障碍。然而，膜渗透机制还不太清楚。为了研究可渗透（和不可渗透）设计的共同特征，有必要通过脂质双层来再现环状肽的膜渗透过程。我们基于定向分子动力学（MD）和复制交换伞状采样模拟，模拟了 100 种六肽环状肽穿过脂质双层的膜渗透过程，并使用非均相溶解-扩散模型及其修改版本来预测膜通透性。此外，我们通过预测 56 种具有不同化学结构的八肽环状肽的膜通透性（包括来自制药公司的一些机密设计），证实了该方案的有效性。结果表明，除了强疏水性肽外，对于肽库，观察到环状肽的实验评估和计算的膜通透性之间存在合理的相关性。我们对 MD 轨迹的分析表明，大多数肽在主体水和膜之间的边界区域稳定存在，对于大多数肽来说，穿过膜中心的过程是膜渗透的主要障碍。该屏障的高度与肽与周围介质之间的静电相互作用很好地相关。还分析了膜内每个垂直位置的代表性肽的结构和能量特征，揭示了肽通过根据周围环境改变其取向和构象来渗透膜。
