Cyclic peptides have regained interest as potential inhibitors of challenging targets, but have often a low bioavailability. The natural product cyclosporine A (CsA) is the textbook exception. Despite its size and polar backbone it is able to passively cross membranes. This ability is hypothesized to be due to a conformational change from the low-energy conformation in water to a "congruent" conformation that is populated both in water and inside the membrane. Here, we use a combination of NMR measurements and kinetic models based on molecular dynamics simulations to rationalize the difference in the membrane permeability of cyclosporine E (CsE) and CsA. The structure of CsE differs only in a backbone methylation, but its membrane permeability is one order of magnitude lower. The most striking difference is found in the interconversion rates between the conformational states favored in water and in chloroform, which are up to one order of magnitude slower for CsE compared to CsA.