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Semi-empirical and Linear-Scaling DFT Methods to Characterize duplex DNA and G-quadruplexes in Presence of Interacting Small Molecules

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.