Biologia

Mg2+ in the Major Groove Modulates B-DNA Structure and Dynamics
´ Marc Gueroult1,2, Olivier Boittin1, Oliver Mauffret3, Catherine Etchebest1, Brigitte Hartmann1,3*
´cules Biologiques, UMR 665 INSERM-Universite Paris Diderot, Sorbonne Paris Cite Institut National de la ´ ´, 1 Dynamique des Structures et Interactions des Macromole ´orique, UPR 9080 CNRS, Institut de Biologie Physico-Chimique,Paris, France, 3 Laboratoire de Biologie Transfusion Sanguine, Paris, France, 2 Laboratoire de Biochimie The ´e, et Pharmacologie Applique UMR 8113 CNRS-ENS de Cachan, Cachan, France

Abstract
This study investigates the effect of Mg2+ bound to the DNA major groove on DNA structure and dynamics. The analysis of a comprehensive dataset of B-DNA crystallographic structures shows that divalentcations are preferentially located in the DNA major groove where they interact with successive bases of (A/G)pG and the phosphate group of 59-CpA or TpG. Based on this knowledge, molecular dynamics simulations were carried out on a DNA oligomer without or with Mg2+ close to an ApG step. These simulations showed that the hydrated Mg2+ forms a stable intra-strand cross-link between the two purines insolution. ApG generates an electrostatic potential in the major groove that is particularly attractive for cations; its intrinsic conformation is well-adapted to the formation of water-mediated hydrogen bonds with Mg2+. The binding of Mg2+ modulates the behavior of the 59-neighboring step by increasing the BII (e-f.0u) population of its phosphate group. Additional electrostatic interactions betweenthe 59-phosphate group and Mg2+ strengthen both the DNA-cation binding and the BII character of the 59-step. Cation binding in the major groove may therefore locally influence the DNA conformational landscape, suggesting a possible avenue for better understanding how strong DNA distortions can be stabilized in protein-DNA complexes.
´roult M, Boittin O, Mauffret O, Etchebest C, Hartmann B (2012)Mg2+ in the Major Groove Modulates B-DNA Structure and Dynamics. PLoS ONE 7(7): Citation: Gue e41704. doi:10.1371/journal.pone.0041704 Editor: Franca Fraternali, King’s College, London, United Kingdom Received April 24, 2012; Accepted June 25, 2012; Published July 23, 2012 ´roult et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, whichpermits Copyright: ß 2012 Gue unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Funding was provided by the Institut National de la Transfusion Sanguine, 6 rue Alexandre Cabanel, 75015 Paris, France. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Competing Interests: The authors have declared that no competing interests exist. * E-mail: bhartman@ens-cachan.fr

Introduction
Specific DNA base-cation interactions have instigated numerous studies (reviewed in [1–3]) because it is presumed that cations can modulate DNA structure in a sequence-dependent manner, thus affecting the readout and packaging of DNA. Most of these studies are devotedto divalent cations because, in contrast to monovalent alkali cations, divalent cations can be unequivocally located in X-ray structures when they are ordered in the lattice [1– 4]. In addition, DNA-cation interactions seem preferentially involve divalent cations – at least Mg2+ – over monovalent cations [5]. Within crystals, hydrated divalent cations frequently mediate intermolecular contactsbetween adjacent DNA molecules. Mg2+, Ca2+, or Mn2+ cross-link DNA bases, especially guanines, to phosphates of neighboring helices [6–14]. Molecular dynamics simulations have shown that Mg2+ stabilizes groove-backbone interactions in right-handed DNA crossovers [15]. Cations mediating intermolecular interactions thus behave as adhesives between helices and may play a biological role in crowded DNA...