Fig. 5: Computational support for dynamic SNAC aggregation in non-polar environments.
From: Permeation enhancer-induced membrane defects assist the oral absorption of peptide drugs
A Self-assembly of 50 SNAC molecules with semaglutide in CH2Cl2 after 50 ns (cyan: protonated SNAC with λ < 0.5; blue: deprotonated SNAC with λ > 0.5). The insets highlight stabilizing interactions between SNAC and titratable peptide residues. See Supplementary Fig. 27B for the corresponding aggregation of just SNAC in CH2Cl2, as well as Supplementary Video 3 and Supplementary Video 4 for the corresponding trajectories. B CpHMD simulation of a SNAC/CTAB micelle highlighting π-stacking interactions of aggregated SNAC molecules in the micelles that are also observed (Fig. 4C/D) in 1H-1H NOESY NMR experiments. SNAC molecules are shown with carbons in opaque cyan, polar hydrogens in white, nitrogens in dark blue, and oxygens in red. CTAB is shown in blue in semi-transparent mode. Key hydrogen atoms observed in the 1H-1H NOESY NMR experiments are highlighted in space-filling mode with H-d shown in magenta, and H-b in light green. C Relationship between the exposed surface area of SNAC molecules (which correlates with the position of SNAC inside the membrane cluster) and the calculated diffusion coefficients D of the corresponding SNAC molecules across the 1 μs membrane simulations (n = 4). This plot clearly shows that mobile SNAC molecules exist both inside and outside the SNAC aggregates in the membrane. D Snapshots of the initial and final frames of the 1 μs membrane simulation (first replica) with all SNAC molecules initially present within 7.5 Å of the semaglutide (red) highlighted in dark blue. These snapshots indicate that the SNAC molecules in the SNAC cluster disperse throughout the SNAC cluster during the simulation, which shows that these SNACs are mobile. See Supplementary Fig. 35B–D for analogous plots of the other three simulation replicas. Additional examples with other dynamic SNAC molecules that are part of a membrane cluster are shown in Supplementary Video 12, Supplementary Video 13, and Supplementary Video 14. Source data are provided as a Source Data file.
