Estimating localization of various statins within a POPC bilayer
Estimating localization of various statins within a POPC bilayer
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DOI：
10.1016/j.chemphyslip.2021.105074
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发表时间：
2021-03-10
影响因子：
3.4
通讯作者：
Klauda, Jeffery B.
中科院分区：
文献类型：
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作者：
Kuba, Jacob Olondo;Yu, Yalun;Klauda, Jeffery B.
他汀类药物作为心脏病患者的一类处方药，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的影响的途径对患者产生有益影响。这些多效性作用在不同的他汀类药物中各不相同，并且越来越多的假设是它们与他汀类药物的定位及其对膜的作用有关。在这项研究中，我们使用分子动力学（MD）模拟与CHARMM 36全原子力场调查的本地化的他汀类药物（阿托伐他汀，西立伐他汀，洛伐他汀，普伐他汀）在POPC双层和他们如何影响的酰基链序参数（S-CD），表面积/脂质（APL），和双层的厚度。从500 ns模拟获得的数据表明，洛伐他汀位于膜中最深处，主要与疏水核心相互作用，西立伐他汀比洛伐他汀稍微更接近双层/溶剂界面，并通过其二羟基酸基团与头部基团相互作用，发现普伐他汀最接近双层/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。他汀类药物差异改变的S-CD和APL和大多数的双层厚度，但这些影响是温和的。总体而言，正如预期的那样，他汀类药物的定位似乎遵循其亲水性，并且鉴于先前的数据显示他汀类药物的疏水性和多效性效应之间的关系，人们会预期定位并与膜的不同区域相互作用的他汀类药物具有不同的效应。这项研究提供了一些重要的洞察他汀类药物定位在一个简化的模型的细胞膜。
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.