Spontaneous Membrane Translocating Peptides

总结 双层的碳氢化合物核心通常是极性或带电的 溶质。我们已经发现了一类新型的阳离子肽，可以有效地穿过这一屏障 而不引起双层透化。这些肽从根本上不同于其他肽。 类膜活性肽，并可能掌握了解如何绕过 烃核心的屏障。然而，这种行为的决定因素是 目前未知。在这里，我们将探讨肽易位的物理化学基础， 全面检查已知易位的合理设计的序列变体， 肽。这个提议的首要假设是，只有当 肽具有特定的能转位的序列基序和最佳的疏水性。 在这里，我们将测试这样的假设，即跨双层的肽易位需要最佳的 疏水性，其确保膜中的低稳态群体，和特定的疏水性， 由两个疏水残基间隔的两个丝氨酸组成的序列基序，嵌入在 疏水序列。我们将确定这些允许易位的重要性， 通过合理的序列修饰独立地改变它们，并评估它们的性质， 对（1）跨双层转运、（2）与双层结合和（3）结构响应的影响 连接到肽上。

Summary The hydrocarbon core of a bilayer is normally a strict barrier to the passage of polar or charged solutes. We have discovered a novel class of cationic peptides that efficiently cross this barrier without causing bilayer permeabilization. These peptides are fundamentally different from other classes of membrane active peptides, and may hold the key to understanding how to bypass the barrier of the hydrocarbon core on demand. Yet, the determinants of this behavior are currently unknown. Here we will explore the physical chemical basis of peptide translocation by comprehensively examining rationally designed sequence variants of a known translocating peptide. The overarching hypothesis of this proposal is that translocation occurs only if the peptides have a specific translocation-enabling sequence motif and optimal hydrophobicity. Here we will test the hypothesis that translocation of peptides across bilayers requires optimal hydrophobicity that ensures a low steady state population in a membrane, and a specific sequence motif consisting of two arginines spaced by two hydrophobic residues, embedded in a hydrophobic sequence. We will determine the importance of these translocation-permissive properties by varying them independently by rational sequence modification and assessing the effect on (1) translocation across bilayers, (2) binding to bilayers, and (3) the structural response of the bilayer to the peptides.