In this work, we investigate the fundamental question of how long polar peptides can directly pass through a membrane with the help of permeation enhancers. By advancing toward this general goal, we aim to enhance the mechanistic understanding of oral peptide drug formulations for polar peptide drugs (see Fig. for an example). This knowledge is needed to help guide the rational design of improved oral formulations for such peptides in the future. Our work contrasts with computational permeability studies of small molecule drugs 2 (Fig. ) and macrocyclic peptides with mostly hydrophobic side chains (Fig. ). For these types of structures, structure-based computational modeling is already able to provide a relatively accurate mechanistic picture of the membrane permeability, especially when coupled with continuous constant pH molecular dynamics (CpHMD) models for small-molecule drugs 2 (Fig. ) and sufficient conformational sampling for macrocyclic peptides (Fig. ). As a result, the passive membrane permeation of small molecules and macrocyclic peptides is reasonably well understood (to the point where rational computational design has become possible ).