Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, USA.
J Phys Chem A. 2013 Feb 21;117(7):1560-8. doi: 10.1021/jp308364d. Epub 2013 Feb 12.
Base stacking is known to make an important contribution to the stability of DNA and RNA, and accordingly, significant efforts are ongoing to calculate stacking energies using ab initio quantum mechanical methods. To date, impressive improvements have been made in the model chemistries used to perform stacking energy calculations, including extensions that include robust treatments of electron correlation with extended basis sets, as required to treat interactions where dispersion makes a significant contribution. However, those efforts typically use rigid monomer geometries when calculating the interaction energies. To overcome this, in the present work, we describe a novel internal coordinate definition that allows the relative, intermolecular orientation of stacked base monomers to be constrained during geometry optimizations while allowing full optimization of the intramolecular degrees of freedom. Use of the novel reference frame to calculate the impact of full geometry optimization versus constraining the bases to be planar on base monomer stacking energies, combined with density-fitted, spin-component scaling MP2 treatment of electron correlation, shows that full optimization makes the average stacking energy more favorable by -3.4 and -1.5 kcal/mol for the canonical A and B conformations of the 16 5' to 3' base stacked monomers. Thus, treatment of geometry optimization impacts the stacking energies to an extent similar to or greater than the impact of current state of the art increases in the rigor of the model chemistry itself used to treat base stacking. Results also indicate that stacking favors the B-form of DNA, though the average difference versus the A-form decreases from -2.6 to -0.6 kcal/mol when the intramolecular geometry is allowed to fully relax. However, stacking involving cytosine is shown to favor the A-form of DNA, with that contribution generally larger in the fully optimized bases. The present results show the importance of allowing geometry optimization, as well as properly treating the appropriate model chemistry, in studies of nucleic acid base stacking.
碱基堆积被认为对 DNA 和 RNA 的稳定性有重要贡献，因此，人们正在努力使用从头算量子力学方法计算堆积能。迄今为止，在用于执行堆积能计算的模型化学中已经取得了令人印象深刻的改进，包括扩展到包括扩展基组的稳健电子相关处理，以处理其中分散作用有重要贡献的相互作用。然而，这些努力在计算相互作用能时通常使用刚性单体几何形状。为了克服这一问题，在本工作中，我们描述了一种新的内部坐标定义，允许在几何优化过程中约束堆叠碱基单体的相对、分子间取向，同时允许完全优化分子内自由度。使用新的参考框架计算完全几何优化与将碱基约束为平面对碱基单体堆积能的影响，结合密度拟合、自旋分量标度 MP2 处理电子相关，表明完全优化使平均堆积能更加有利，对于 16 个 5' 到 3' 碱基堆叠单体的典型 A 和 B 构象，分别有利 -3.4 和 -1.5 kcal/mol。因此，几何优化处理对堆积能的影响程度与用于处理碱基堆积的模型化学本身的严格程度的最新进展的影响相当或更大。结果还表明，堆积有利于 DNA 的 B 构象，尽管当允许分子内几何形状完全松弛时，与 A 构象的平均差异从 -2.6 减小到 -0.6 kcal/mol。然而，涉及胞嘧啶的堆积有利于 DNA 的 A 构象，在完全优化的碱基中，这种贡献通常更大。本结果表明，在研究核酸碱基堆积时，允许几何优化以及正确处理适当的模型化学非常重要。
