Most protein–protein interactions occur inside cells. Peptides can inhibit protein–protein interactions but tend not to enter cells. We systematically compare cell permeability for 8–12 residue model peptides with helix-inducing lactam/hydrocarbon linkers between amino acid sidechains. Cell uptake increases when hydrophobic residues and lactam linkers (i, i + 4) form a contiguous hydrophobic surface patch. Uptake increases further when both hydrophobic and positively charged (but not neutral or negative) residues are clustered into like surface patches. Amphipathicity alone is however insufficient for cell uptake of acyclic sequences. Changing the linker from lactam to hydrocarbon further increases uptake, but also promotes cell lysis. Helicity, positive charge and amphipathicity together promote cell permeability. Most known bioactive helical peptides do not optimally cluster residues for amphipathicity and so are likely unoptimised for cell uptake.

中文翻译：

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短螺旋约束肽中连续的疏水性和带电表面补丁驱动细胞通透性†

大多数蛋白质之间的相互作用发生在细胞内部。肽可以抑制蛋白质之间的相互作用，但往往不会进入细胞。我们系统地比较了8-12个残基模型肽与氨基酸侧链之间的螺旋诱导内酰胺/碳氢化合物接头的细胞通透性。当疏水性残基和内酰胺连接子（i，i+ 4）形成连续的疏水表面贴剂。当疏水性和带正电（但不是中性或负性）的残基都聚集到类似的表面斑块中时，摄入量会进一步增加。然而，仅两亲性不足以吸收非环序列的细胞。将接头从内酰胺改变为碳氢化合物可进一步增加摄取，但也可促进细胞裂解。螺旋，正电荷和两亲性共同促进细胞通透性。对于两亲性，大多数已知的生物活性螺旋肽不能最佳地聚集残基，因此对于细胞摄取而言可能未优化。