The electronic-structure theory of a large-molecular system in solution: Application to the intercalation of proflavine with solvated DNA Norio Yoshida a,b , Yasuomi Kiyota b , Fumio Hirata a,b, ⁎ a Department of Theoretical and Computational Molecular Science, Institute for Molecular Science, Okazaki 444-8585, Japan b Department of Functional Molecular Science, The Graduate University of Advanced Studies, Okazaki 444-8585, Japan abstract article info Available online 27 April 2010 Keywords: QM/MM RISM DNA DFT 3D-RISM A new approach for investigating solvent effects on the electronic structure of solvated macromolecules is proposed. The method is constructed by combining the quantum and molecular mechanics (QM/MM) methods with the reference interaction site model (RISM) theory. The system treated with the method is divided into three regions, quantum and molecular mechanical regions of solute, and the solvent region. The two solute regions are treated by the ordinary QM/MM method, while the solvent region is handled with the RISM theory. The method is applied to investigate the intercalation of proflavine to two types of decameric B-DNA, namely [deca(dG-dC)] 2 and [deca(dA-dT)] 2 . Our results indicate that the affinity of intercalation of proflavine to the dG-dC base sequence is higher than that of the dA-dT DNA base sequence, which is consistent with the experimental results. The drastic change of solvation structure due to the intercalation makes large positive change in the solvation free energy which is attributed to the dehydration penalty of PR, the screening of electrostatic interaction between PR and DNA, and the hydrophobic interaction of elongated DNA chain. © 2010 Elsevier B.V. All rights reserved. 1. Introduction The electronic structure of macromolecules has attracted a lot of attention in the field of chemistry, physics, biophysics and pharma- cology [1]. Since any of those systems contains many electrons, it is difficult to evaluate the electronic structure of a whole system. One of the most popular approaches is the hybridized quantum and mo- lecular mechanics (QM/MM) methods [2–9]. The strategy of the QM/ MM method is to partition a large molecular system into a small, chemically active part where a reaction may occur, and a larger, chemically inactive part. The chemically active part is treated with QM, while the larger inactive part is treated with MM. In some prob- lems, a cluster of solvent molecules around a target solute is also described in terms of MM. The solvent effect on macromolecules is of another serious con- cern in the field of life science [10,11]. It is because all biomolecules are playing their role in aqueous environment, and any theoretical development regarding life phenomena should treat solvent effect properly [12]. The simplest way to treat solvent effect is to consider solvent molecules around solute as the MM molecules as mentioned above. Although this approach has been popularly applied to various problems, it has a few drawbacks. First, the number of solvent mol- ecule required to reproduce the solvent effect is unclear. Second, this method could not fully sample the configurational space of solvent, because solvent molecules have large degrees of freedom and span a large configurational space. The polarizable continuum model (PCM) also provides a popular approach for evaluating solvent effects on a molecule in solutions [10,11]. However, it has obvious limitations coming from an intrinsic nature of the model, or “macroscopic.” It is unable to describe solute– solvent interactions which require a molecular description, such as hydrogen bonding. Another method for considering the solvent effect is provided by the statistical mechanical theory of molecular liquids based on the Ornstein–Zernike (OZ) integral equation theory, such as the molecular OZ equation, the reference interaction site model (RISM) theory, and the three-dimensional (3D) RISM theory [13–18]. Based on those theories, one can describe microscopic solute–solvent interactions such as a hydrogen bond, and solvent distributions with a complete ensemble average in the thermodynamic limit. The 3D-RISM is one of the most powerful tools to treat the solvation structure and the solvent effect on a macromolecule such as protein. The theory has been successfully applied to such problems as probing water molecules caged in protein, ion binding by protein, and the permeation of water through aquaporin [19–23]. The integral equation theories have been combined with the ab initio electronic structure theory and successfully applied to chemical processes in solutions [24–27]. The RISM self consistent field (RISM- SCF) theory proposed by Ten-no, Hirata, and Kato employs the RISM Journal of Molecular Liquids 159 (2011) 83–92 ⁎ Corresponding author. Department of Theoretical and Computational Molecular Science, Institute for Molecular Science, Okazaki 444-8585, Japan. Tel.: +81 564 55 7314; fax: +81 564 53 4660. E-mail address: hirata@ims.ac.jp (F. Hirata). 0167-7322/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.molliq.2010.04.019 Contents lists available at ScienceDirect Journal of Molecular Liquids journal homepage: www.elsevier.com/locate/molliq