Partitioning and localization of environment-sensitive 2-(2'-pyridyl)- and 2-(2'-pyrimidyl)-indoles in lipid membranes: a joint refinement using fluorescence measurements and molecular dynamics simulations.
Partitioning and localization of environment-sensitive 2-(2'-pyridyl)- and 2-(2'-pyrimidyl)-indoles in lipid membranes: a joint refinement using fluorescence measurements and molecular dynamics simulations.
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DOI：
10.1021/jp106981c
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发表时间：
2010-10-28
影响因子：
3.3
通讯作者：
Ladokhin, Alexey S.
中科院分区：
文献类型：
--
作者：
Kyrychenko, Alexander;Wu, Feiyue;Thummel, Randolph P.;Waluk, Jacek;Ladokhin, Alexey S.
环境敏感染料的荧光被广泛应用于生物分子的局部结构和溶剂化动力学的监测。结果表明，与母体吲哚荧光团相比，2-（2′-吡啶基）-5-甲基吲哚（5 M-PyIn-0）和2-[2′-（4′，6 ′-二甲基嘧啶基）]-吲哚（DMPmIn-0）的荧光对与质子配体的氢键非常敏感.在非极性和极性非质子溶剂中观察到的这些化合物的强荧光在水溶液中被有效地猝灭。这项研究表明，5 M-PyIn-0和DMPmIn-0，这是几乎在水溶液中不发光，成为高度荧光滴定后，与磷脂囊泡。荧光增强伴随着发射最大值的显著蓝移。膜分配的吉布斯自由能（通过从水环境转移到脂质双层过程中稳态荧光强度的增加来测量）对两种化合物都非常有利，范围为-7.1至-8.0 kcal/mol，仅轻微取决于膜的脂质组成。膜分配后的荧光增强指示激发的荧光团和水分子之间的特定氢键相互作用的损失，导致在大量水中的有效荧光淬灭。这一结论得到了原子分子动力学（MD）模拟的支持，表明5 M-PyIn-0和DMPmIn-0都能快速结合并深入分配到脂质双层中。MD模拟还显示了一个快速的，纳秒级的减少在被动扩散的探针分子从散装水到脂质双层的溶质-溶剂氢键的概率。在平衡条件下，5 M-PyIn-0和DMPmIn-0都倾向于在双层的疏水无水区域内深度定位。一个自由能分布的渗透整个双层使用MD伞采样估计表明，这两个吲哚衍生物有利于居住在一个相当宽的势能阱位于10-15毫米的双层中心。
Fluorescence of environment-sensitive dyes is widely applied to monitor local structure and solvation dynamics of biomolecules. It has been shown that, in comparison with a parent indole fluorophore, fluorescence of 2-(2′-pyridyl)-5-methylindole (5M-PyIn-0) and 2-[2′-(4′,6′-dimethylpyrimidyl)]-indole (DMPmIn-0) is remarkably sensitive to hydrogen bonding with protic partners. Strong fluorescence, observed for these compounds in nonpolar and polar aprotic solvents, is efficiently quenched in aqueous solution. This study demonstrates that 5M-PyIn-0 and DMPmIn-0, which are almost nonemitting in aqueous solution, become highly fluorescent upon titrating with phospholipid vesicles. The fluorescence enhancement is accompanied by a significant blue shift of emission maximum. The Gibbs free energy of membrane partitioning, measured by the increase in the steady-state fluorescence intensities during transfer from an aqueous environment to a lipid bilayer, is very favorable for both compounds, being in a range from −7.1 to −8.0 kcal/mol and depending only slightly on lipid composition of the membrane. The fluorescence enhancement upon membrane partitioning is indicative of the loss of the specific hydrogen-bonding interactions between the excited fluorophore and water molecules, causing efficient fluorescence quenching in bulk water. This conclusion is supported by atomistic molecular dynamics (MD) simulations, demonstrating that both 5M-PyIn-0 and DMPmIn-0 bind rapidly and partition deeply into a lipid bilayer. MD simulations also show a rapid, nanosecond-scale decrease in the probability of solute–solvent hydrogen bonding during passive diffusion of the probe molecules from bulk water into a lipid bilayer. At equilibrium conditions, both 5M-PyIn-0 and DMPmIn-0 prefer deep localization within the hydrophobic, water-free region of the bilayer. A free energy profile of penetration across a bilayer estimated using MD umbrella sampling shows that both indole derivatives favor residence in a rather wide potential energy well located 10–15 Å from the bilayer center.
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