Savelyev Alexey, MacKerell Alexander D
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland , Baltimore, Maryland 21201, United States.
J Chem Theory Comput. 2015 Sep 8;11(9):4473-85. doi: 10.1021/acs.jctc.5b00508. Epub 2015 Aug 26.
Recently, we reported the differential impact of the monovalent cations Li(+), Na(+), K(+), and Rb(+) on DNA conformational properties. These were identified from variations in the calculated solution-state X-ray DNA spectra as a function of the ion type in solvation buffer in MD simulations using our recently developed polarizable force field based on the classical Drude oscillator. Changes in the DNA structure were found to mainly involve variations in the minor groove width. Because minor groove dimensions vary significantly in protein-DNA complexes and have been shown to play a critical role in both specific and nonspecific DNA readout, understanding the origins of the observed differential DNA modulation by the first-group monovalent ions is of great biological importance. In the present study, we show that the primary microscopic mechanism for the phenomenon is the formation of water-mediated hydrogen bonds between solvated cations located inside the minor groove and simultaneously to two DNA strands, a process whose intensity and impact on DNA structure depends on both the type of ion and the DNA sequence. Additionally, it is shown that the formation of such ion-DNA hydrogen bond complexes appreciably modulates the conformation of the backbone by increasing the population of the BII substate. Notably, the differential impact of the ions on DNA conformational behavior is only predicted by the Drude polarizable model for DNA with virtually no effect observed from MD simulations utilizing the additive CHARMM36 model. Analysis of dipole moments of the water shows the Drude SWM4 model to possess high sensitivity to changes in the local environment, which indicates the important role of electronic polarization in the salt-dependent conformational properties. This also suggests that inclusion of polarization effects is required to model even relatively simple biological systems, such as DNA, in various ionic solutions.
最近，我们报道了单价阳离子Li(+)、Na(+)、K(+)和Rb(+)对DNA构象性质的不同影响。这些影响是通过计算溶液态X射线DNA光谱的变化来确定的，该变化是在分子动力学（MD）模拟中，作为溶剂化缓冲液中离子类型的函数，使用我们最近基于经典德鲁德振子开发的可极化力场得到的。发现DNA结构的变化主要涉及小沟宽度的变化。由于小沟尺寸在蛋白质-DNA复合物中差异很大，并且已被证明在特异性和非特异性DNA读出中都起着关键作用，因此了解第一族单价离子对DNA的不同调节作用的起源具有重要的生物学意义。在本研究中，我们表明该现象的主要微观机制是位于小沟内的溶剂化阳离子与两条DNA链同时形成水介导的氢键，该过程的强度及其对DNA结构的影响取决于离子类型和DNA序列。此外，研究表明，这种离子-DNA氢键复合物的形成通过增加BII亚态的数量，明显调节了主链的构象。值得注意的是，离子对DNA构象行为的不同影响仅由德鲁德可极化模型预测，而使用加性CHARMM36模型的MD模拟几乎没有观察到影响。对水的偶极矩分析表明，德鲁德SWM4模型对局部环境的变化具有高灵敏度，这表明电子极化在盐依赖性构象性质中起着重要作用。这也表明，即使是相对简单的生物系统，如各种离子溶液中的DNA，在建模时也需要考虑极化效应。
