To account for all the weakly ionizable functional groups in our system (with ~400 ionizable groups in SNAC and 11 in semaglutide), we utilized a scalable CpHMD model implemented in GROMACS. This CpHMD model, which achieved approximately 80% of the performance speed of a regular MD simulation, is essential to provide accurate, environment-dependent pKa values and environment-dependent charges for the complex peptide/permeation-enhancer/lipid-bilayer interactions in this system. Our simulations revealed a more even distribution of SNAC between the membrane and water layer compared to classical simulations with a fixed protonation state model, enabling SNAC to act as a detergent in the water layer while at the same time facilitating peptide drug permeation within the membrane. Specifically, a 1-μs unbiased CpHMD simulation (likely the largest CpHMD model constructed to date) shows that SNAC aggregates around semaglutide in both the interior and the exterior of the membrane. These aggregates form dynamic, partially fluid SNAC-filled membrane defects that can enable passive semaglutide permeation across the membrane by a mechanism reminiscent of quicksand. Additional support for dynamic SNAC aggregation in nonpolar environments was obtained through CpHMD simulations in CH2Cl2, as well as diffusion-ordered spectroscopy (DOSY), NMR titrations, and dynamic light scattering (DLS) experiments in CDCl3, an established mimic of the hydrophobic membrane interior. Collectively, these results suggest a new, plausible molecular mechanism for passive membrane permeation with transcellular permeation enhancers, which we anticipate will aid in the rational design of new oral peptide drug formulations in the future.