半经验和线性标度DFT方法表征相互作用小分子存在下的双链体DNA和G-四链体
Semi-empirical and Linear-Scaling DFT Methods to Characterize duplex DNA and G-quadruplexes in Presence of Interacting Small Molecules
摘要：
DNA及其与配体相互作用的计算研究是一个高度相关的研究领域，对开发新的治疗策略具有重大影响。然而，这种大型和复杂系统的计算描述需要考虑不同类型的相互作用。所有这些考虑都意味着计算化学面临着真正的挑战。使用量子方法的整个系统需要大量的计算资源，在并行化和优化的理论策略的改进。计算方法，如LS-DFT和DLPNO-CCSD（T），可以允许在合理的计算时间内执行从头计算QM计算，包括明确的大型生物系统的电子结构。在这项工作中，我们研究了小分子和阳离子与DNA的相互作用（DNA和G-四链体），比较不同的计算方法：LMKLL/DZDP理论水平上的线性标度DFT（LS-DFT），半经验方法（PM 6-DH 2和PM 7），混合QM/MM，和DLPNO-CCSD（T）。我们的目标是证明LS-DFT的充分性，以处理不同类型的相互作用存在于DNA依赖的系统。我们表明，LMKLL/DZDP使用SIESTA可以产生非常准确的几何形状和能量在所有不同的系统中考虑这项工作：双链体DNA（dDNA），邻菲咯啉插入dDNA，G-四链体，金属-G-四分体考虑不同大小的碱金属。据我们所知，这是第一次，全G-四重体的几何优化已经进行了使用DFT方法由于其线性缩放能力。此外，我们表明，LS-DFT提供了高质量的结构，和一些半经验哈密顿量也可以产生合适的几何。然而，DLPNO-CCSD（T）和LS-DFT是唯一准确描述我们研究中考虑的所有系统的相互作用能的方法。
英文摘要：
The computational study of DNA and its interaction with ligands is a highly relevant area of research, with significant consequences for developing new therapeutic strategies. However, the computational description of such large and complex systems requires considering interactions of different types. All these considerations imply a real challenge for computational chemistry. Using quantum methods for the entire system requires significant computational resources, with improvements in parallelization and optimization of theoretical strategies. Computational methods, such as LS-DFT and DLPNO-CCSD(T), may allow performing ab initio QM calculations, including explicitly the electronic structure for large biological systems, at a reasonable computing time. In this work, we study the interaction of small molecules and cations with DNA (duplex-DNA and G-quadruplexes), comparing different computational methods: a linear-scaling DFT (LS-DFT) at LMKLL/DZDP level of theory, semi-empirical methods (PM6-DH2 and PM7), mixed QM/MM, and DLPNO-CCSD(T). Our goal is to demonstrate the adequacy of LS-DFT to treat the different types of interactions present in DNA-dependent systems. We show that LMKLL/DZDP using SIESTA can yield very accurate geometries and energetics in all the different systems considered in this work: duplex DNA (dDNA), phenanthroline intercalating dDNA, G-quadruplexes, and Metal-G-tetrads considering alkaline metals of different sizes. As far as we know, this is the first time that full G-quadruplex geometry optimizations have been carried out using a DFT method thanks to its linear-scaling capabilities. Moreover, we show that LS-DFT provides high-quality structures, and some semi-empirical Hamiltonian can also yield suitable geometries. However, DLPNO-CCSD(T) and LS-DFT are the only methods that accurately describe interaction energies for all the systems considered in our study.
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