探究血清素 1A 受体脂质相互作用的能量分布。

IF 3.3 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Madhura Mohole , Amit Naglekar , Durba Sengupta , Amitabha Chattopadhyay
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引用次数: 0

摘要

G 蛋白偶联受体(GPCR)是受脂质调控的跨膜蛋白,在细胞信号传导和药理学中发挥着核心作用。虽然膜脂质在 GPCR 功能中的作用已得到公认,但由于 GPCR 与脂质相互作用的复杂性,尚未从热力学角度对这些相互作用进行表征。在这项研究中,我们通过对嵌入复杂膜中的血清素 1A 受体进行粗粒度模拟,估算了脂质结合的能量学和动力学。我们发现,脂质与受体结合的能量为 1-4 kT,时间尺度为 1-10 μs。胆固醇、糖蛋白脂质 GM1、磷脂酰乙醇胺(PE)和磷脂酰丝氨酸(PS)脂质的能量最高,停留时间最长。接触概率的多指数拟合表明了不同的动态机制,分别对应于 ps、ns 和 μs 时间尺度,我们将其与环状、中间和非环状脂质位点相关联。尽管脂质结合的能量相对较弱,但其时间尺度却与高阻抗高度相对应。我们的研究结果突出表明,GPCR-脂质相互作用是由热力学相互作用和脂质结合的动力学特征共同驱动的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Probing the energy landscape of the lipid interactions of the Serotonin1A receptor

Probing the energy landscape of the lipid interactions of the Serotonin1A receptor

G protein-coupled receptors (GPCRs) are lipid-regulated transmembrane proteins that play a central role in cell signaling and pharmacology. Although the role of membrane lipids in GPCR function is well established, the underlying GPCR-lipid interactions have not been thermodynamically characterized due to the complexity of these interactions. In this work, we estimate the energetics and dynamics of lipid association from coarse-grain simulations of the serotonin1A receptor embedded in a complex membrane. We show that lipids bind to the receptor with varying energetics of 1–4 kT, and timescales of 1–10 μs. The most favorable energetics and longest residence times are observed for cholesterol, glycosphingolipid GM1, phosphatidylethanolamine (PE) and phosphatidylserine (PS) lipids. Multi-exponential fitting of the contact probability suggests distinct dynamic regimes, corresponding to ps, ns and μs timescales, that we correlate with the annular, intermediate and non-annular lipid sites. The timescales of lipid binding correspond to high barrier heights, despite their relatively weaker energetics. Our results highlight that GPCR-lipid interactions are driven by both thermodynamic interactions and the dynamical features of lipid binding.

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来源期刊
Biophysical chemistry
Biophysical chemistry 生物-生化与分子生物学
CiteScore
6.10
自引率
10.50%
发文量
121
审稿时长
20 days
期刊介绍: Biophysical Chemistry publishes original work and reviews in the areas of chemistry and physics directly impacting biological phenomena. Quantitative analysis of the properties of biological macromolecules, biologically active molecules, macromolecular assemblies and cell components in terms of kinetics, thermodynamics, spatio-temporal organization, NMR and X-ray structural biology, as well as single-molecule detection represent a major focus of the journal. Theoretical and computational treatments of biomacromolecular systems, macromolecular interactions, regulatory control and systems biology are also of interest to the journal.
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