The mechanism by which a long polar peptide like semaglutide integrates into a membrane while preserving its structural integrity amidst the influence of a permeation enhancer remains an enigmatic process. To investigate this process, we have now made use of all-atom CpHMD simulations (with all the ionizable groups of the peptide and the permeation enhancers treated with a variable protonation state model). Notably, the pKa values of ionizable sites can change drastically in or near a membrane 2 and/or during complexation/aggregate formation, and CpHMD simulations are an accurate way to capture such environment-dependent effects on the charges of the peptides and the permeation enhancers. Foundational work by the Swanson lab has shown that such effects are key to accurately model the membrane permeation of small-molecule drugs. Yet, prior CpHMD simulations have been limited to smaller systems with fewer ionizable functional groups mostly due to unfavorable scaling of the simulation cost with increasing number of ionizable sites. With the advent of scalable CpHMD models, we have now been able to extend this type of simulation to larger systems. Our work likely represents the largest CpHMD simulation system run to date (with over 400 ionizable functional groups treated at the CpHMD level). Below, the detailed results of these CpHMD simulations are provided together with experimental evidence, all supporting our proposed quicksand-like permeation mechanism for polar peptides. show SNAC spontaneously incorporating into the membrane, in agreement with prior results obtained with fixed protonation state models. However, with the CpHMD methodology, we now find that SNAC dynamically ionizes in the aqueous phase and then neutralizes to pass through the lipid bilayer membrane (see also Supplementary Fig. ). This Co-Aggregation of SNAC and Semaglutide in the Aqueous Phase. Next, with a larger CpHMD system containing 50 SNACs in a water box, we found that SNAC rapidly aggregates around semaglutide (Fig. ) in water. These simulations also demonstrated that the protonation states of SNAC and semaglutide during co-aggregation are strongly influenced by the interactions between SNAC and semaglutide, as well as interactions with other SNAC molecules. This result further highlights the need for a CpHMD model to capture these dynamic, environment-dependent effects.