Connecting Hydrophobic Surfaces in Cyclic Peptides Increases Membrane Permeability

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