Fig. 3: Impact of dynamic protonation on the membrane insertion of the permeation enhancer SNAC.
From: Permeation enhancer-induced membrane defects assist the oral absorption of peptide drugs
A Self-assembly of 50 SNAC molecules (all treated with the CpHMD model) with semaglutide in aqueous solution after 50 ns (cyan: protonated SNAC (λ < 0.5); blue: deprotonated SNAC (λ > 0.5)). See Supplementary Video 4 for the trajectory of this self-assembly process. The inset highlights an ionic interaction between a deprotonated SNAC molecule and R36 of semaglutide, which illustrates how the peptide environment affects the pKa and with it the dominant protonation state of SNAC. B Plot of the λ-coordinate for the SNAC molecule that forms the salt bridge with R36. This ionic interaction stabilizes the deprotonated (λ = 1) state for SNAC resulting in a local pKa of ~3.4 (calculated based on the Henderson–Hasselbach equation). Source data are provided as a Source Data file.
