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A Multidimensional B-Spline Correction for Accurate Modeling Sugar Puckering in QM/MM Simulations

机译：多维B样条校正可在QM / MM仿真中精确建模糖起皱

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The computational efficiency of approximate quantum mechanical methods allows their use for the construction of multidimensional reaction free energy profiles. It has recently been demonstrated that quantum models based on the neglect of diatomic differential overlap (NNDO) approximation have difficulty modeling deoxyribose and ribose sugar ring puckers and thus limit their predictive value in the study of RNA and DNA systems. A method has been introduced in our previous work to improve the description of the sugar puckering conformational landscape that uses a multidimensional B-spline correction map (BMAP correction) for systems involving intrinsically coupled torsion angles. This method greatly improved the adiabatic potential energy surface profiles of DNA and RNA sugar rings relative to high-level ab initio methods even for highly problematic NDDO-based models. In the present work, a BMAP correction is developed, implemented, and tested in molecular dynamics simulations using the AM1/d-PhoT semiempirical Hamiltonian for biological phosphoryl transfer reactions. Results are presented for gas-phase adiabatic potential energy surfaces of RNA transesterification model reactions and condensed-phase QM/MM free energy surfaces for nonenzymatic and RNase A-catalyzed transesterification reactions. The results show that the BMAP correction is stable, efficient, and leads to improvement in both the potential energy and free energy profiles for the reactions studied, as compared with ab initio and experimental reference data. Exploration of the effect of the size of the quantum mechanical region indicates the best agreement with experimental reaction barriers occurs when the full CpA dinucleotide substrate is treated quantum mechanically with the sugar pucker correction.
机译：近似量子力学方法的计算效率允许它们用于构建多维反应自由能分布图。最近已经证明，基于忽略双原子微分重叠（NNDO）近似的量子模型难以建模脱氧核糖和核糖糖环折叠，因此限制了它们在RNA和DNA系统研究中的预测价值。在我们以前的工作中已经引入了一种方法来改进对糖褶皱构象景观的描述，该方法对涉及内在耦合扭转角的系统使用多维B样条校正图（BMAP校正）。相对于高水平的从头算方法，该方法极大地改善了DNA和RNA糖环的绝热势能表面轮廓，即使对于基于NDDO的模型存在很大问题。在当前的工作中，开发了BMAP校正，并在分子动力学模拟中使用AM1 / d-PhoT半经验哈密顿量对生物磷酸基转移反应进行了测试。给出了RNA酯交换反应模型的气相绝热势能表面和非酶催化和RNase A催化的酯交换反应的缩合QM / MM自由能表面的结果。结果表明，与从头算和实验参考数据相比，BMAP校正稳定，有效，并且导致所研究反应的势能和自由能曲线均得到改善。对量子力学区域大小影响的探索表明，当用糖褶皱校正对全部CpA二核苷酸底物进行量子力学处理时，与实验反应障碍的最佳吻合发生了。

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