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.

作为给心脏病患者开的一类药物，他汀类药物是世界上最受欢迎的处方药之一。多年来，他汀类药物已被证明通过独立于其对胆固醇影响的途径对患者产生有益影响。这些多效作用因不同的他汀类药物而异，并且越来越多的假设认为它们与他汀类药物在膜中的定位及其对膜的影响有关。在这项研究中，我们使用分子动力学 (MD) 模拟和 CHARMM36 全原子力场来研究他汀类药物（阿托伐他汀、西立伐他汀、洛伐他汀和普伐他汀）在 POPC 双层中的定位以及它们如何影响酰基链顺序参数（小号_CD)、每脂质表面积 (APL) 和双层厚度。从 500 ns 模拟中获得的数据表明，洛伐他汀位于膜的最深处，主要与疏水核相互作用，西立伐他汀比洛伐他汀更靠近双层/溶剂界面，并通过其二羟基酸基团与头基相互作用，而普伐他汀是发现最接近双层/溶剂界面，其疏水环主要与酰基羰基周围的区域相互作用，其二羟基酸与溶剂和头基相互作用。由于自聚集，在我们的模拟过程中没有观察到阿托伐他汀与双层的一致结合。他汀类药物不同程度地改变S _CD和 APL 以及大多数双层厚度，但这些影响不大。总的来说，正如预期的那样，他汀类药物的定位似乎遵循其亲水性，并且鉴于之前的数据显示他汀类药物的疏水性和多效性作用之间的关系，人们会预期定位于膜不同区域并与不同区域相互作用的他汀类药物会产生不同的效果。这项研究为细胞膜简化模型中他汀类药物的定位提供了一些重要的见解。