Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement, LAMBE UMR8587 CNRS, Université d'Evry val d'Essonne, boulevard F. Mitterrand, Bat. Maupertuis, 91025 Evry Cedex, France.
J Am Chem Soc. 2010 Dec 29;132(51):18067-77. doi: 10.1021/ja103759v. Epub 2010 Dec 8.
The role of water in the structural change of nicotine from its inactive form in the gas phase to its bioactive form in aqueous solution has been investigated by two complementary theoretical approaches, i.e., geometry optimizations and molecular dynamics. Structures of the lowest-energy nicotineH(+)-(H(2)O)(n) complexes protonated either on the pyridine (inactive form) or pyrrolidine (active form) ring have been calculated, as well as the free-energy barriers for the proton-transfer tautomerization between the two cycles. These structures show chains of 2-4 water molecules bridging the two protonation sites. The room-temperature free-energy barrier to tautomerization along the minimum-energy path from the pyridine to the pyrrolidine cycle drops rapidly when the number of water molecules increases from 0 to 4, but still remains rather high (16 kJ/mol with four water molecules), indicating that the proton transfer is a rather difficult and rare event. We compare results obtained through this explicit water molecule approach to those obtained by means of continuum methods. Car-Parrinello molecular dynamics (CPMD) simulations of the proton-transfer process in bulk with explicit water molecules have been conducted at room temperature. No spontaneous proton transfers have been observed during the dynamics, and biased CPMD simulations have therefore been performed in order to measure the free-energy profile of the proton transfer in the aqueous phase and to reveal the proton-transfer mechanism through water bridges. The MD bias involves pulling the proton from the pyridine ring to the surrounding bulk. Dynamics show that this triggers the tautomerization toward the pyrrolidine ring, proceeding without energy barrier. The proton transfer is extremely fast, and protonation of the pyrrolidine ring was achieved within 0.5 ps. CPMD simulations confirmed the pivotal role played by the water molecules that bridge the two protonation sites of nicotine within the bulk of the surrounding water.
已通过两种互补的理论方法，即几何优化和分子动力学，研究了水在尼古丁从气相中不活跃形式到水相中的生物活性形式的结构变化中的作用。已计算出在吡啶（不活跃形式）或吡咯烷（活性形式）环上质子化的最低能量尼古丁 H(+)-(H(2)O)(n) 配合物的结构，以及两个环之间质子转移互变异构的自由能垒。这些结构显示出由 2-4 个水分子组成的链桥接两个质子化位点。从吡啶环到吡咯烷环的最小能量路径上的互变异构的室温自由能垒随着水分子数从 0 增加到 4 而迅速下降，但仍然相当高（4 个水分子时为 16 kJ/mol），表明质子转移是一个相当困难和罕见的事件。我们将通过这种显式水分子方法获得的结果与通过连续体方法获得的结果进行了比较。已在室温下用显式水分子对质子转移过程进行了 Car-Parrinello 分子动力学（CPMD）模拟。在动力学过程中没有观察到自发的质子转移，因此进行了有偏 CPMD 模拟，以测量质子在水相中的自由能分布，并揭示质子通过水桥的转移机制。MD 偏置涉及将质子从吡啶环拉到周围的本体。动力学表明，这会引发向吡咯烷环的互变异构，而无需能量垒。质子转移非常快，在 0.5 ps 内完成了吡咯烷环的质子化。CPMD 模拟证实了水分子在尼古丁的两个质子化位点之间在周围水本体中桥接所起的关键作用。
