Ji Jingjing, Lyman Edward
Department of Physics and Astronomy, University of Delaware, Newark, DE, USA.
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, USA.
Faraday Discuss. 2025 May 8. doi: 10.1039/d4fd00210e.
We report simulations and analysis of the A adenosine receptor in its fully active state, in two different membrane environments. The first is a model in which the lipids are distributed asymmetrically according to recent lipidomics, simulations, and biophysical measurements, which together establish the distribution of lipids and cholesterol between the two leaflets. The second is the symmetrized version, which captures the membrane state following loss of lipid asymmetry. By comparing lipid-protein interactions between these two cases we show that solvation by phosphatidyl serine (PS) is insensitive to the loss of asymmetry-an abundance of positively charged sidechains around the cytoplasmic side of the receptor enriches solvation by PS in both membrane states. Cholesterol interactions are sensitive to the loss of asymmetry, with the abundance of cholesterol in the exoplasmic leaflet driving long-lived cholesterol interactions in the asymmetric state. However, one cholesterol interaction site on helix 6 is observed in both cases, and was also observed in earlier work with different membrane models, supporting its identification as a cholesterol binding site.
我们报告了在两种不同膜环境中处于完全活性状态的A1腺苷受体的模拟和分析。第一种是一种模型，其中脂质根据最近的脂质组学、模拟和生物物理测量结果不对称分布，这些共同确定了脂质和胆固醇在两个小叶之间的分布。第二种是对称版本，它捕获了脂质不对称性丧失后的膜状态。通过比较这两种情况下的脂-蛋白相互作用，我们表明磷脂酰丝氨酸（PS）的溶剂化对不对称性的丧失不敏感——受体细胞质侧周围大量带正电荷的侧链在两种膜状态下都丰富了PS的溶剂化作用。胆固醇相互作用对不对称性的丧失敏感，外质小叶中胆固醇的丰度驱动了不对称状态下长期的胆固醇相互作用。然而，在两种情况下都观察到了螺旋6上的一个胆固醇相互作用位点，并且在早期使用不同膜模型的工作中也观察到了该位点，这支持将其鉴定为胆固醇结合位点。
