Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
J Phys Chem B. 2013 Jul 18;117(28):8322-9. doi: 10.1021/jp401414y. Epub 2013 Jul 3.
Molecular dynamics calculations have been used to determine the structure of phosphatidylinositol 4,5 bisphosphate (PIP2) at the quantum level and to quantify the propensity for PIP2 to bind two physiologically relevant divalent cations, Mg(2+) and Ca(2+). We performed a geometry optimization at the Hartree-Fock 6-31+G(d) level of theory in vacuum and with a polarized continuum dielectric to determine the conformation of the phospholipid headgroup in the presence of water and its partial charge distribution. The angle between the headgroup and the acyl chains is nearly perpendicular, suggesting that in the absence of other interactions the inositol ring would lie flat along the cytoplasmic surface of the plasma membrane. Next, we employed hybrid quantum mechanics/molecular mechanics (QM/MM) simulations to investigate the protonation state of PIP2 and its interactions with magnesium or calcium. We test the hypothesis suggested by prior experiments that binding of magnesium to PIP2 is mediated by a water molecule that is absent when calcium binds. These results may explain the selective ability of calcium to induce the formation of PIP2 clusters and phase separation from other lipids.
分子动力学计算已被用于在量子水平上确定磷脂酰肌醇 4,5 二磷酸（PIP2）的结构，并定量测量 PIP2 与两种生理相关的二价阳离子（Mg2+和 Ca2+）结合的倾向。我们在真空和极化连续介电质中进行了 Hartree-Fock 6-31+G(d)理论的几何优化，以确定磷脂头部基团在水存在下的构象及其部分电荷分布。头部基团与酰基链之间的角度几乎垂直，表明在没有其他相互作用的情况下，肌醇环将沿质膜的细胞质表面平躺。接下来，我们采用混合量子力学/分子力学（QM/MM）模拟来研究 PIP2 的质子化状态及其与镁或钙的相互作用。我们检验了先前实验提出的假设，即镁与 PIP2 的结合是由一个水分子介导的，而当钙结合时，这个水分子不存在。这些结果可以解释钙选择性地诱导 PIP2 簇形成和与其他脂质相分离的能力。
