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Connecting Hydrophobic Surfaces in Cyclic Peptides Increases Membrane Permeability
Author(s) -
Hoang Huy N.,
Hill Timothy A.,
Fairlie David P.
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202012643
Subject(s) - substituent , chemistry , permeability (electromagnetism) , membrane , hydrogen bond , polar , membrane permeability , stereochemistry , molecule , organic chemistry , biochemistry , physics , astronomy
Abstract 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.