(197z) Permeation of Glycoside Molecules through Lipid Bilayers

Saponins are glycosides ubiquitously distributed in the plant kingdom. They have received extensive attention for their potential medicinal value. Recent studies showed that their biological activities are closely modulated by interaction with lipid bilayers. For example, membrane permeation, can directly affect the passive diffusion of saponins, which is also the dominant pathway for saponins to pass through the intestinal tract, blood vessel wall, or other human tissues. Undoubtedly, the absorption of saponin will be directly related to its medicinal efficacy, and clarification of this permeation process is of great interest to the pharmaceutical industry. Here, we combined molecular dynamics simulations with transition-tempered metadynamics to study the permeation process of a monosaccharide saponin (SAM). The time-structure based independent component analysis (tICA) was also applied to design collective variables to accelerate the convergence of free energy profile calculation. Simulations allowed us to characterize the permeation details of saponin through lipid bilayers, which primarily occurs by both hydrophilic interactions of SAM sugar group with lipid headgroups and hydrophobic interactions between SAM aglycone ring and lipid tails. We tentatively proposed the following general permeation mechanism: initially, due to the hydrophilic interaction between the SAM sugar group and lipid headgroups, the molecule approaches the bilayer surface. Then, SAM flips into the bilayer core because of the hydrophobic interaction of SAM aglycone with lipid tails. As the simulation progresses, SAM gradually moves down to the other leaflet and flips again such that its sugar group points towards the lipid/water interface. Finally, through interaction with water, SAM is pulled out of the bilayer. During the permeation process, the lipid bilayer deforms, and water molecules penetrate into hydrophobic core as the SAM flips between leaflets. We carry simulations with different membrane models and found that lipid species modulate the permeation mechanism, resulting in different free energy profiles. In summary, this work provides insights about the permeation process of saponin through lipid bilayers at the atomistic level. Understanding the passive diffusion mechanism of small molecules can also contribute to decrease the cost and time of developing novel antibiotic and anticancer treatments.