Article pubs.acs.org/JCTC Understanding the Chemistry of Lead at a Molecular Level: The Pb(II) 6s6p Lone Pair Can Be Bisdirected in Proteins Marie-Celiné Van Severen,*,§ Ulf Ryde,‡ Olivier Parisel,† and Jean-Philip Piquemal† † Laboratoire de Chimie Theorique,́ UPMC, CC 137, 4 place Jussieu, 75252 Paris, Cedex 05, France and CNRS, UMR 7616, CC 137, 4 place Jussieu, 75252, Paris Cedex 05, France ‡ Theoretical Chemistry, Lund University, P.O. Box 124, 22100 Lund, Sweden § Department of Chemistry - Ångström Laboratory, Theoretical Chemistry, Uppsala University, Sweden ABSTRACT: Pb2+ complexes can attain several different topologies, depending of the shape of the Pb 6s6p lone pair. In this paper, we study structures with a bisdirected Pb lone pair with quantum mechanics (DFT) and QM/MM calculations. We study small symmetric Pb2+ models to see what factors are needed to get a bisdirected lone pair. Two important mechanisms have been found: First, the repulsion of the lone pair of Pb2+ with other lone pairs in the equatorial plane leads to a bisdirected structure. Second, a bisdirected lone pair can also arise due to interactions with double bonds, lone pairs, or hydrogen atoms. Moreover, we have analyzed Pb2+ sites in proteins and to see if a bisdirected lone pair can exist in an asymmetrical environment. Several instances of bisdirected lone pairs were discovered. ■ INTRODUCTION not possible, due to strong steric and electrostatic interactions The toxicity of lead has been known since antiquity, and for between the ligands, holodirectional complexes are recovered, mammals its ingestion results in the well-known disease and the lone pair loses its stereochemical activity. saturnism. Experiments indicate that two types of Pb2+ In a recent paper, we showed that the lone-pair organization can be even more complex: We observed a third possible complexes exist: holo- and hemidirected organizations (see 4 Figure 1).1 This structural difference is caused by the peculiar organization of the 6s6p lone pair, called bisdirected (see capably of the Pb 6s6p lone pair to adapt to the presence of Figure 1c). In this case, the lone pair is split in two ligands.2 Hemidirected complexes arise when Pb2+ has ligands hemispheres. Such a topological structure was obtained when Pb was bound to a plane and symmetric molecule. In this study, in one hemisphere, letting the lone pair expand in the opposite 2+ direction. This extension of the lone pair can cause structural we investigate when the lone pair of Pb will be bisdirected, what factors favor this structure, if such a topological structure variations in protein chelation sites and perturbs its native fl structure, leading to the possible loss of activity.3 When this is could exist within proteins where the symmetry and atness are absent. To address such issues, we analyze the behavior of the lone pair of Pb2+ in different environments using the electron localization function (ELF) analysis to visualize the extension of the lone pair and natural bond orbital (NBO) to find the corresponding atomic occupations. ■ RESULTS In this article, we will study bisdirected Pb2+ 6s6p lone pairs in various structures. We use the topological analysis method ELF because it is a powerful tool to localize and visualize regions in the space where electrons are the most or less localized based on the excess of kinetic energy of the electrons compared to a Figure 1. Three different topological structures of the lone pair of homogenized gas of electrons. This gives rise to basins that Pb2+. The red color is used for a basin that belongs to only one atom. show excess of electrons like lone pairs or bonds. Those basins The green color is used for basin shared by two atoms, and the blue are defined by an isosurface (with a value between 0 and 1). color is for the hydrogen + the covalent bond H−X with X = any atoms. On the righ,t the basin of Pb2+ and the basin of H are not colored. Received: June 23, 2012 Published: April 9, 2013 © 2013 American Chemical Society 2416 dx.doi.org/10.1021/ct300524v | J. Chem. Theory Comput. 2013, 9, 2416−2424 Journal of Chemical Theory and Computation Article Figure 2. ELF representation of 1,4,7,10,13,16-hexaoxa-cyclooctadeca-2,5,8,11,14,17 hexaene (HCOH) replaced by six water molecules with the same position of the oxygens as in HCOH. Figure 3. Schematic and ELF representations of complex A. Violet color is for the basin of Pb2+, the pink color for the basin of the oxygens that point inside the cycle, and the blue color for the basin of oxygens that point outside the cycle. The higher it is, the thinner the basin is. For instance, if the HCOH consists of six oxygen atoms alternating with six CC value of the isosurface is 0, then there will be a big basin double bonds. To understand if the shape of the lone pair of including the entire molecule, with no details on what kind of Pb2+ is induced by the oxygens or the double bonds, we have bonds or lone pair there is in this molecule. If the isosurface is designed the systems shown in Figure 2. We kept the same 0.8, for example, then all the lone pairs and the bonds will be place for the oxygens as in the HCOH system, but we deleted visible by their corresponding basins. And at 1, there are no the double bonds and replaced the carbon atoms with hydrogen basins left. So in particular ELF can show the basin atoms. Thus, the complex is now formed by six water molecules corresponding to the valence lone pair of Pb2+ called V(Pb). with the oxygen atoms located in the same place as the oxygen In this study, all the isosurfaces are taken at 0.8, except when atoms in HCOH in Figure 1c. specified. First, we study series of nonexistent molecules From the ELF analysis in Figure 3a, it is obvious that the designed to have special features in order to get some insight lone pair of Pb2+ is still bisdirected. It seems that this structure on the structure and the composition of ligands that give rise to is caused by the repulsion of the lone pairs of oxygen atoms. To the bisdirected structure. Those molecules are symmetric, but exclude the possibility that the bisdirected structure is linked to we are interested in asymmetric environment as well. Second, the direction of the water molecules, another calculation was we focus on protein systems coming from a PDB structure carried out with the hydrogen atoms directed vertically to plane where we kept only a few atoms around Pb2+. No optimization with the Pb and O atoms (see Figure 3b). However, the ELF of our systems at this stage has been done because the only analysis shows that the lone pair of Pb2+ is still bisdirected. This information wanted at this stage of the study is to know if the indicates that the Pb2+ lone pair will be bisdirected in structures bisdirected structure can exist in a system where the atoms are where some atoms induce repulsion in a plane. in a “random” way around Pb2+. Third, we use more advance A NBO (Natural Bond Orbital) analysis has been carried out methods (MD and QM/MM calculations) in a protein to detect any difference in the population in the p orbitals of environment to see if this structure still exists. Pb2+ in those systems. Table 1 shows electronic populations of Bisdirected Lone Pairs in Model Complexes. Here, we the donor orbitals: 2p of O and 1s of H and the acceptor 6p will focus on four different complexes and their derived orbitals of Pb2+. complexes: 1,4,7,10,13,16-hexaoxa-cyclooctadeca-2,5,8,11,14,17 As the 6s of Pb2+ is already full, the occupation of 6p orbitals 2+ hexaene (HCOH) in Figure 1c, the Pb(C16H16O16) complex is important because they will receive the electron for the 2+ 2+ (complex A) in Figure 3, Pb(C18H24) complex (complex B) environment. It can be seen that the lone pair of Pb in the in Figure 8, and a tested series of cyclic ligands constructed HCOH complex has a higher population than in the complexes from merged benzene rings. with water molecules. The oxygen orbitals of this complex have The first time the bisdirected structure was observed was in lower populations than the water complexes because of the the system shown in the Figure 1c. This chelating ligand more polar bonds in the water molecules. 2417 dx.doi.org/10.1021/ct300524v | J. Chem. Theory Comput. 2013, 9, 2416−2424 Journal of Chemical Theory and Computation Article Table 1. NBO Analysis of the Bisdirected Structures in Figures 2 and 3 for Only One Oxygen and One Hydrogen in the Different System ligand Pb(p) O(p) H(s) HCOH (see Figure 1c) 0.50 4.96 0.73 (H2O)6 planar (see Figure 2a) 0.19 5.27 0.45 (H2O)6 perpendicular hydrogens (Figure 2b) 0.22 5.32 0.40 This example is not enough to settle why the bisdirected structure is observed. Further evidence can be obtained by using a second molecule that is of toroidal shape. Therefore, we 2+ studied the Pb(C16H16O16) complex (complex A) in Figure 3. In this new system, the oxygen atoms are placed in planes that Figure 5. ELF representation of the optimized structure of 2+ 2+ are under and above Pb . [Pb(H2O)8] . The lone pair of Pb(II) is holodirected. As can be seen from the ELF analysis, again the lone pair of Pb2+ is bisdirected.