Department of Computer Science, Virginia Tech, Blacksburg, Virginia 24061, USA.
Computational Biology, Biological Sciences Division, Pacific Northwest National Laboratory, Richland, Washington 99352, USA.
J Chem Phys. 2018 May 21;148(19):195101. doi: 10.1063/1.5027260.
The ion atmosphere around highly charged nucleic acid molecules plays a significant role in their dynamics, structure, and interactions. Here we utilized the implicit solvent framework to develop a model for the explicit treatment of ions interacting with nucleic acid molecules. The proposed explicit ions/implicit water model is based on a significantly modified generalized Born (GB) model and utilizes a non-standard approach to define the solute/solvent dielectric boundary. Specifically, the model includes modifications to the GB interaction terms for the case of multiple interacting solutes-disconnected dielectric boundary around the solute-ion or ion-ion pairs. A fully analytical description of all energy components for charge-charge interactions is provided. The effectiveness of the approach is demonstrated by calculating the potential of mean force for Na-Cl ion pair and by carrying out a set of Monte Carlo (MC) simulations of mono- and trivalent ions interacting with DNA and RNA duplexes. The monovalent (Na) and trivalent (CoHex) counterion distributions predicted by the model are in close quantitative agreement with all-atom explicit water molecular dynamics simulations used as reference. Expressed in the units of energy, the maximum deviations of local ion concentrations from the reference are within . The proposed explicit ions/implicit water GB model is able to resolve subtle features and differences of CoHex distributions around DNA and RNA duplexes. These features include preferential CoHex binding inside the major groove of the RNA duplex, in contrast to CoHex biding at the "external" surface of the sugar-phosphate backbone of the DNA duplex; these differences in the counterion binding patters were earlier shown to be responsible for the observed drastic differences in condensation propensities between short DNA and RNA duplexes. MC simulations of CoHex ions interacting with the homopolymeric poly(dA·dT) DNA duplex with modified (de-methylated) and native thymine bases are used to explore the physics behind CoHex-thymine interactions. The simulations suggest that the ion desolvation penalty due to proximity to the low dielectric volume of the methyl group can contribute significantly to CoHex-thymine interactions. Compared to the steric repulsion between the ion and the methyl group, the desolvation penalty interaction has a longer range and may be important to consider in the context of methylation effects on DNA condensation.
高度荷电的核酸分子周围的离子氛围在其动力学、结构和相互作用中起着重要作用。在这里，我们利用隐溶剂框架开发了一种模型，用于明确处理与核酸分子相互作用的离子。所提出的显式离子/隐式水模型基于一个经过显著修改的广义 Born (GB) 模型，并利用非标准方法来定义溶质/溶剂介电边界。具体来说，该模型包括对多个相互作用的溶质-断开介电边界的 GB 相互作用项进行修改，例如围绕溶质-离子或离子-离子对的介电边界。为电荷-电荷相互作用的所有能量分量提供了完全解析的描述。通过计算 Na-Cl 离子对的平均力势能，并对单价（Na）和三价（CoHex）抗衡离子与 DNA 和 RNA 双链相互作用的一组蒙特卡罗（MC）模拟，证明了该方法的有效性。模型预测的单价（Na）和三价（CoHex）抗衡离子分布与用作参考的全原子显式水分子动力学模拟非常吻合。以能量单位表示，局部离子浓度与参考值的最大偏差在 以内。所提出的显式离子/隐式水 GB 模型能够解析 CoHex 分布在 DNA 和 RNA 双链周围的细微特征和差异。这些特征包括 CoHex 在 RNA 双链的大沟内的优先结合，而不是 CoHex 在 DNA 双链的糖-磷酸骨架的“外部”表面上的结合；这些抗衡离子结合模式的差异以前被证明是导致短 DNA 和 RNA 双链之间观察到的凝聚倾向差异的原因。使用带有修饰（去甲基化）和天然胸腺嘧啶碱基的同聚物聚（dA·dT）DNA 双链与 CoHex 离子相互作用的 MC 模拟来探索 CoHex-胸腺嘧啶相互作用背后的物理机制。模拟表明，由于靠近低介电体积的甲基基团，离子去溶剂化的罚则可以显著贡献于 CoHex-胸腺嘧啶相互作用。与离子和甲基基团之间的空间排斥相比，去溶剂化的罚则相互作用具有更长的作用范围，并且在考虑甲基化对 DNA 凝聚的影响时可能很重要。
