Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 2, 8093 Zürich, Switzerland.
Novartis Institutes for BioMedical Research, Novartis Pharma AG, Novartis Campus, 4056 Basel, Switzerland.
J Med Chem. 2023 Feb 23;66(4):2773-2788. doi: 10.1021/acs.jmedchem.2c01837. Epub 2023 Feb 10.
Cyclic peptides extend the druggable target space due to their size, flexibility, and hydrogen-bonding capacity. However, these properties impact also their passive membrane permeability. As the "journey" through membranes cannot be monitored experimentally, little is known about the underlying process, which hinders rational design. Here, we use molecular simulations to uncover how cyclic peptides permeate a membrane. We show that side chains can act as "molecular anchors", establishing the first contact with the membrane and enabling insertion. Once inside, the peptides are positioned between headgroups and lipid tails─a unique polar/apolar interface. Only one of two distinct orientations at this interface allows for the formation of the permeable "closed" conformation. In the closed conformation, the peptide crosses to the lower leaflet via another "anchoring" and flipping mechanism. Our findings provide atomistic insights into the permeation process of flexible cyclic peptides and reveal design considerations for each step of the process.
环状肽由于其大小、灵活性和氢键结合能力，扩展了可成药的靶标空间。然而，这些特性也影响了它们的被动膜通透性。由于无法通过实验监测“穿越”膜的过程，人们对潜在的过程知之甚少，这阻碍了合理的设计。在这里，我们使用分子模拟来揭示环状肽如何穿透膜。我们表明，侧链可以作为“分子锚”，与膜建立最初的接触并允许插入。一旦进入，肽就位于头部基团和脂质尾部之间——这是一个独特的极性/非极性界面。在该界面上只有两种不同取向中的一种允许形成可渗透的“闭合”构象。在闭合构象中，肽通过另一种“锚定”和翻转机制穿过下叶。我们的研究结果为柔性环状肽的渗透过程提供了原子水平的见解，并揭示了该过程每个步骤的设计考虑因素。
