Connecting Hydrophobic Surfaces in Cyclic Peptides Increases Membrane Permeability,Angewandte Chemie International Edition

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Connecting Hydrophobic Surfaces in Cyclic Peptides Increases Membrane Permeability
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2020-11-13 , DOI: 10.1002/anie.202012643
Huy N Hoang ₁ , Timothy A Hill ₁ , David P Fairlie _{1,

2}

Affiliation

N‐ or C‐methylation in natural and synthetic cyclic peptides can increase membrane permeability, but it remains unclear why this happens in some cases but not others. Here we compare three‐dimensional structures for cyclic peptides from six families, including isomers differing only in the location of an N‐ or Cα‐methyl substituent. We show that a single methyl group only increases membrane permeability when it connects or expands hydrophobic surface patches. Positional isomers, with the same molecular weight, hydrogen bond donors/acceptors, rotatable bonds, calculated LogP, topological polar surface area, and total hydrophobic surface area, can have different membrane permeabilities that correlate with the size of the largest continuous hydrophobic surface patch. These results illuminate a key local molecular determinant of membrane permeability.

中文翻译：

连接环肽中的疏水表面可增加膜的渗透性

天然和合成环肽中的N-或C-甲基化可以增加膜的通透性，但尚不清楚为什么在某些情况下会发生这种情况，而在其他情况下则不会。在这里，我们比较了六个家族的环状肽的三维结构，包括仅在N-或Cα-甲基取代基位置上不同的异构体。我们表明，单个甲基仅在连接或扩展疏水表面补丁时才增加膜的渗透性。具有相同分子量，氢键供体/受体，可旋转键，计算得出的LogP，拓扑极性表面积和总疏水表面积的位置异构体可以具有与最大连续疏水表面补丁大小相关的不同膜渗透率。这些结果阐明了膜渗透性的关键局部分子决定因素。

更新日期：2020-11-13

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