Division of Physical Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
J Phys Chem A. 2010 Apr 1;114(12):4375-87. doi: 10.1021/jp9110019.
Cardiolipin is a key lipid component in many biological membranes. Proton conduction and proton-lipid interactions on the membrane surface are thought to be central to mitochondrial energy production. However, details on the cardiolipin headgroup structure are lacking and the protonation state of this lipid at physiological pH is not fully established. Here we present ab initio DFT calculations of the cardiolipin (CL) headgroup and its 2'-deoxy derivative (dCL), with the aim of establishing a connection between structure and acid-base equilibrium in CL. Furthermore, we investigate the effects of solvation on the molecular conformations. In our model, both CL and dCL showed a significant gap between the two pK(a) values, with pK(a2) above the physiological range, and intramolecular hydrogen bonds were found to play a central role in the conformations of both molecules. This behavior was also observed experimentally in CL. Structures derived from the DFT calculations were compared with those obtained experimentally, collected for CL in the Protein Data Bank, and conformations from previous as well as new molecular dynamics simulations of cardiolipin bilayers. Transition states for proton transfer in CL were investigated, and we estimate that protons can exchange between phosphate groups with an approximate 4-5 kcal/mol barrier. Computed NMR and IR spectral properties were found to be in reasonable agreement with experimental results available in the literature.
心磷脂是许多生物膜中的关键脂质成分。质子传导和质子-脂质相互作用被认为是线粒体能量产生的核心。然而，心磷脂头基结构的细节缺乏，并且这种脂质在生理 pH 值下的质子化状态尚未完全确定。在这里，我们提出了心磷脂 (CL) 头基及其 2'-脱氧衍生物 (dCL) 的从头算 DFT 计算，旨在建立 CL 中的结构与酸碱平衡之间的联系。此外，我们研究了溶剂化对分子构象的影响。在我们的模型中，CL 和 dCL 都显示出两个 pK(a) 值之间的显著差距，pK(a2) 值高于生理范围，并且发现分子内氢键在心磷脂的两种构象中都起着核心作用。这种行为在 CL 中也进行了实验观察。从 DFT 计算中得出的结构与从实验中获得的结构、从蛋白质数据库中收集的 CL 的结构以及以前和新的心磷脂双层分子动力学模拟的构象进行了比较。还研究了 CL 中质子转移的过渡态，我们估计磷酸基团之间的质子可以以约 4-5 kcal/mol 的能垒进行交换。计算的 NMR 和 IR 光谱性质与文献中可用的实验结果具有合理的一致性。
