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 simultaneously in a balanced way, such as non-covalent weak interactions (namely hydrogen bonds and stacking), metal–ligand interactions, polarisation and charge transfer effects. All these considerations imply a real challenge for computational chemistry. The possibility of studying large biological systems using quantum methods for the entire system requires significant computational resources, with improvements in parallelisation and optimisation of theoretical strategies. Computational methods, such as Linear-Scaling Density Functional Theory (LS-DFT) and DLPNO-CCSD(T), may allow performing ab initio quantum mechanics calculations, including the electronic structure for large biological systems, in a reasonable computing time. In this work, we study the interaction of small molecules and cations with DNA (both duplex DNA and G-quadruplexes), comparing different computational methods: a LS-DFT method at the 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 optimisations 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 Hamiltonians 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.
This research was financially supported by Diputación Foral de Gipuzkoa through the Gipuzkoa Fellows Program to A. G. This research was also financially supported by the Fundação para a Ciência e a Tecnologia (FCT) by means of Projects PTDC/QUI-QFI/29236/2017, UIDB/04046/2020, and UIDP/04046/2020 and by the Spanish Ministry of Economy, Industry and Competitiveness under the Maria de Maeztu Units of Excellence Program/MDM-2016-0618). A. G. is thankful to ARAID – Fundación Agencia Aragonesa para la Investigación y el Desarrollo for current funding in the frame of ARAID researchers. The authors also thank for technical and human support provided by IZO-SGI (SGIker) of UPV/EHU and European funding (ERDF and ESF). Financial support comes also from Eusko Jaurlaritza (Basque Government) through the project IT1254-19 and IT1584-22, from Spanish MICINN through Grant No. PID2019-107338RB-C61/AEI/10.13039/501100011033, and grant PGC2018-099321-B-100 from the Ministry of Science, Innovation and Universities through the Office of Science Research (MINECO/FEDER). Pseudopotentials and Numerical Atomic Orbitals Basis Dataset for SIESTA were provided by Simune Atomistics S. L. (www.simuneatomistics.com). S. E. thanks the Ministry of Higher Education and Scientific Research of Tunisia for the funding of intership carried out in Portugal and Spain. I. O. D. L. is also very grateful to CICnanoGUNE BRTA for his PhD grant.