Toward a full structural characterization of G-quadruplex DNA in aqueous solution: Molecular dynamics simulations of four G-quadruplex molecules Ming-Hui Li, Quan Luo, Xiang-Gui Xue, Ze-Sheng Li * Institute of Theoretical Chemistry, State Key Laboratory of Theoretical and Computational Chemistry, Jilin University, Changchun 130023, People’s Republic of China article info Article history: Received 15 December 2009 Received in revised form 15 April 2010 Accepted 25 April 2010 Available online 20 May 2010 Keywords: MD Quadruplex Backbone torsion angle Glycosidic torsion angle Sugar pucker abstract A systematic study on guanine (G) quadruplex DNA flexibility was performed by using extended explicit molecular dynamics (MD) simulations on four quadruplex molecules containing one dimeric and three monomeric G-quadruplexes with the most used and recent modified versions of AMBER force fields (parm99 and parmbsc0). The detailed analyses of general structure and basic structural parameters were done for the G-DNA structures. The results indicate that parmbsc0 provides a slightly better description for the G-DNA stems than parm99, and the situation is the opposite for the loops. Many backbone tor- sions located in the non-canonical regions are not retained in both simulations. Most of the glycosidic torsion angles of loop bases deviate largely from the experimental values. Many phase angles of pseudo- rotation of the sugar rings are transformed to other puckers. The transformation of structural parameters given by each force field is useful as direction for further improving force field of polynucleotide structures. Ó 2010 Elsevier B.V. All rights reserved. 1. Introduction G-rich DNA sequences can fold in the presence of monovalent cations to form a four-stranded structure named G-quadruplex, which is stabilized via Hoogsteen hydrogen bonding between a planar arrangement of four guanine nucleobases, named G-tetrad [1,2]. G-quadruplexes are highly polymorphic, which can form tet- rameric, dimeric or monomeric G-quadruplexes, respectively, according to the orientation of the strands, the glycosidic confor- mation of guanines and loop connectivities [3,4]. The strands of dimeric and monomeric G-quadruplexes are connected by various loop conformations: double-chain-reversal loops, edgewise loops and diagonal loops. G-quadruplex DNA molecules are considered to be the most interesting non-canonical DNA systems, as G-rich sequences have the potential to take these structures in several biologically important DNA regions, such as telomere, promoter and regions associated with human disease [5,6]. Thereby, G-quad- ruplex has spawned a large number of experimental and theoreti- cal investigations aimed at appreciation of their role in biological regulation as well as their potential to serve as novel drugs and drug targets [7–11]. Computational studies are now used widely, which allow for a description of DNA structure and dynamics at the atomic level. Many molecular dynamics simulations have been performed for the detailed studies of the structural, energetic, and dynamic prop- erties of quadruplex and quadruplex complex [9–11]. The simula- tion results can complement experimental work and provide more in-depth and comprehensive understanding for G-DNA. Recently, Sponer et al. carried out a set of extended explicit solvent molecu- lar dynamics simulations on two quadruplex DNA molecules, using several versions of AMBER force fields (parmbsc0 and parm99) and the CHARMM27 force field [12]. Their results indicate that none of the available force fields at present is accurate enough to describe the G-DNA loops. Among the force fields, parmbsc0 provides re- sults that are closest to the experimental target values but still not in full agreement. Up to date, few researches have been carried out to investigate the flexibility of G-DNA structures, while a number of MD simulations have been applied to investigate the flexibility of duplex DNA in detail [13–15]. Furthermore, G-quadru- plexes cannot be simulated accurately as helix DNA in the present available force fields. Therefore, the detailed and full structural characterization of G-quadruplex DNA is very necessary for the moment. In this paper, extended explicit MD simulations were performed on four representative quadruplex conformations that contain one dimeric and three monomeric G-quadruplexes using parm99 and parmbsc0 force field, respectively. The basic structural parameters (Backbone torsion angles, glycosidic torsion angles and sugar puck- er) were analyzed in detail. Our detailed investigation to the basic structural parameters of four representative conformations can characterize the flexibility of G-DNA and find the reasons why the G-DNA could not be simulated accurately. 0166-1280/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.theochem.2010.04.035 * Corresponding author. E-mail address: zeshengli@hit.edu.cn (Z.-S. Li). Journal of Molecular Structure: THEOCHEM 952 (2010) 96–102 Contents lists available at ScienceDirect Journal of Molecular Structure: THEOCHEM journal homepage: www.elsevier.com/locate/theochem