Connecting Hydrophobic Surfaces in Cyclic Peptides Increases Membrane Permeability.

Huy N Hoang, Timothy A Hill, David P Fairlie

Angewandte Chemie (International ed. in English) 2021 Apr 06

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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. © 2020 Wiley-VCH GmbH.

Citation

Huy N Hoang, Timothy A Hill, David P Fairlie. Connecting Hydrophobic Surfaces in Cyclic Peptides Increases Membrane Permeability. Angewandte Chemie (International ed. in English). 2021 Apr 06;60(15):8385-8390