Anionic Lipid and Cholesterol Interactions with α4β2 nAChR: Insights from MD Simulations
Anionic Lipid and Cholesterol Interactions with α4β2 nAChR: Insights from MD Simulations
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DOI：
10.1021/jp900714b
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发表时间：
2009-05-14
影响因子：
3.3
通讯作者：
Tang, Pei
中科院分区：
文献类型：
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作者：
Cheng, Mary H.;Xu, Yan;Tang, Pei
阴离子脂质和胆固醇（CHOL）对烟碱乙酰胆碱受体（nAChR）的功能至关重要。我们通过在1-棕榈酰-2-油酰磷脂酰胆碱（POPC）、1-棕榈酰-2-油酰磷脂酸（POPA）和CHOL的比例为3：1：1的三元脂质混合物中超过10 ns的分子动力学模拟研究了它们与开放和闭合通道α 4 β 2 nAChR的相互作用（Haddadian等人，J. Phys. Chem. B 2008，112，13981）。平均有65和74个界面脂质周围的封闭和开放通道α 4 β 2乙酰胆碱受体，分别在平衡的模拟系统。在开放通道系统中，42%的界面POPA的酰基链部分插入到内部或intersubunit腔，相比之下，只有7%的封闭通道α 4 β 2。在单个亚基的空腔内没有发现CHOL，但有一些CHOL渗入亚基之间的间隙。由于POPA的头基较小，它可以进入一些POPC由于空间排斥而不易到达的非环状位点。此外，POPA不仅作为受体的氢键（氢键）的POPC一样，但也作为一个供体，通过其羟基的氢键与蛋白质的主链。POPA的带电头基允许脂质在α 4 β 2的跨膜（TM）和细胞外（EC）或细胞内（IC）结构域的界面处与保守的Arg和Lys残基形成稳定的盐桥。在开放系统中发现POPA和α 4 β 2 nAChR之间的盐桥和氢键（H键）的数量高于封闭系统，表明POPA在不同通道状态之间的平衡中的潜在作用。大多数界面POPA分子表现出较低的顺序参数比本体POPA由于混合效应的笨拙缺陷，疏水性失配，和附近的魔角的脂质取向。这些独特的性质使界面POPA能够实现POPC无法实现的与蛋白质的特异性相互作用，从而使POPA对nAChR的功能至关重要。
Anionic lipids and cholesterols (CHOL) are critical to the function of nicotinic acetylcholine receptors (nAChR). We investigated their interactions with an open- and closed-channel alpha 4 beta 2 nAChR by over 10 ns molecular dynamics simulations in a ternary lipid mixture of 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), 1-palmitoyl-2-oleoyl phosphatidic acid (POPA), and CHOL with a ratio of 3:1:1 (Haddadian et al., J. Phys. Chem. B 2008, 112, 13981). On average there were 65 and 74 interfacial lipids around the closed- and open-channel alpha 4 beta 2 nAChR, respectively, in the equilibrated simulation systems. In the open-channel system, 42% of the interfacial POPA had acyl chains partially inserted into intra- or intersubunit cavities, as compared to only 7% in the closed-channel alpha 4 beta 2. No CHOL was found in cavities within single subunits, though some CHOL infiltrated into the gaps between subunits. Because of its smaller headgroup, POPA could access some nonannular sites where POPC could not easily reach due to steric exclusion. Furthermore, POPA acted not only as an acceptor for hydrogen bonding (H bonding) as POPC did, but also as a donor through its hydroxyl group for H bonding with the backbone of the protein. The charged headgroup of POPA allowed the lipid to form stable salt bridges with conserved Arg and Lys residues at the interfaces of the transmembrane (TM) and extracellular (EC) or intracellular (IC) domains of the alpha 4 beta 2. A higher number of salt bridges and hydrogen bonds (H bonds) between POPA and the alpha 4 beta 2 nAChR were found in the open system than in the closed system, suggesting a potential role of POPA in the equilibrium between different channel states. Most interfacial POPA molecules showed lower order parameters than the bulk POPA due to the mixed effect of gauche defects, hydrophobic mismatch, and the lipid orientations near the magic angle. These unique properties enable the interfacial POPA to achieve what POPC cannot with regard to specific interactions with the protein, thereby making POPA essential for the function of nAChR.