Estimating localization of various statins within a POPC bilayer.

As a class of drugs prescribed to heart disease patients, statins are among the most popular prescription drugs in the world. Over the years, statins have been shown to have beneficial effects on patients via pathways independent of their effect on cholesterol. These pleiotropic effects vary across the different statins, and a growing hypothesis is that they are related to the localization of the statins in and their effect on the membrane. In this study, we use molecular dynamics (MD) simulations with the CHARMM36 all-atom force field to investigate the localization of statins (atorvastatin, cerivastatin, lovastatin, and pravastatin) in a POPC bilayer and how they affect the acyl chain order parameters (S _CD ), surface area per lipid (APL), and thicknesses of the bilayer. The data obtained from 500 ns simulations suggests that lovastatin is localized deepest in the membrane, mostly interacting with the hydrophobic core, cerivastatin is slightly closer to the bilayer/solvent interface than lovastatin and interacts with the headgroups via its dihydroxy acid group, and pravastatin is found closest to the bilayer/solvent interface, its hydrophobic rings interacting mostly with the region around the acyl's carbonyl and its dihydroxy acid interacting with the solvent and the headgroups. Consistent binding of atorvastatin to the bilayer is not observed during our simulation due to self-aggregation. The statins differentially alter the S _CD and APL and most of the bilayer thicknesses, but these effects are modest. Overall, as expected, the localization of statins seems to follow their hydrophilicity, and given previous data showing the relationship between statins' hydrophobicity and pleiotropic effects, one would expect statins that localize and interact with different regions of the membrane to have different effects. This research provides some important insight into statin localization in a simplified model of a cellular membrane.
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