Fig. 6: Unbiased CpHMD Simulations showing semaglutide spontaneously adhering to and incorporating into the membrane in the presence of SNAC.

The model contained semaglutide (red), 60% POPC lipids (yellow/grey), 40% cholesterol (pink), and 400 SNAC molecules (cyan: protonated with λ < 0.5; blue: deprotonated with λ > 0.5). A 100-ns CpHMD simulation during which a SNAC-semaglutide aggregate spontaneously forms and adsorbs to the membrane surface. B 1-μs CpHMD simulation, which was started from a snapshot with semaglutide’s fatty acid tail anchored in the membrane. After a few hundred nanoseconds semaglutide spontaneously starts to sink into the SNAC defects formed inside the membrane as the peptide drug is getting buried by SNAC molecules moving from the center of the membrane toward the semaglutide. Similar behavior was also observed in three additional replicas generated from different random seeds (including two replicas with a different initial starting conformation with the lipid tail buried less deep in the membrane). Movies of all trajectories are included as Supplementary Video 11, Supplementary Video 12, Supplementary Video 13, Supplementary Video 14, and Supplementary Video 15.