The serotonin_1A receptor belongs to the superfamily of G protein-coupled receptors (GPCRs) and is a potential drug target in neuropsychiatric disorders. The receptor has been shown to require membrane cholesterol for its organization, dynamics and function. Although recent work suggests a close interaction of cholesterol with the receptor, the structural integrity of the serotonin_1A receptor in the presence of cholesterol has not been explored. In this work, we have carried out all atom molecular dynamics simulations, totaling to 3 μs, to analyze the effect of cholesterol on the structure and dynamics of the serotonin_1A receptor. Our results show that the presence of physiologically relevant concentration of membrane cholesterol alters conformational dynamics of the serotonin_1A receptor and, on an average lowers conformational fluctuations. Our results show that, in general, transmembrane helix VII is most affected by the absence of membrane cholesterol. These results are in overall agreement with experimental data showing enhancement of GPCR stability in the presence of membrane cholesterol. Our results constitute a molecular level understanding of GPCR-cholesterol interaction, and represent an important step in our overall understanding of GPCR function in health and disease.

血清素_1A受体属于G蛋白偶联受体（GPCR）的超家族，是神经精神疾病的潜在药物靶标。该受体已被证明需要膜胆固醇来实现其组织，动力学和功能。尽管最近的工作表明胆固醇与受体的紧密相互作用，但尚未探索在胆固醇存在下血清素_1A受体的结构完整性。在这项工作中，我们进行了总计3μs的所有原子分子动力学模拟，以分析胆固醇对血清素_1A的结构和动力学的影响受体。我们的结果表明，生理相关浓度的膜胆固醇的存在改变了血清素_1A受体的构象动力学，并平均降低了构象波动。我们的结果表明，一般而言，跨膜螺旋VII受膜胆固醇的缺乏影响最大。这些结果与实验数据总体一致，该实验数据显示了在膜胆固醇存在下GPCR稳定性的增强。我们的结果构成了对GPCR-胆固醇相互作用的分子水平的理解，并代表了我们对GPCR在健康和疾病中功能的整体理解的重要一步。