Understanding Selectivity of Hard and Soft Metal Cations within Biological Systems Using the Subvalence Concept. 1. Application to Blood Coagulation: Direct CationProtein Electronic Effects versus Indirect Interactions through Water Networks

Following a previous study by de Courcy et al. (Interdiscip. Sci. Comput. Life Sci. 2009, 1, 55-60), we demonstrate in this contribution, using quantum chemistry, that metal cations exhibit a specific topological signature in the electron localization of their density interacting with ligands according to their “soft” or “hard” character. Introducing the concept of metal cation subvalence, we show that a metal cation can split its outer-shell density (the so-called subvalent domains or basins) according to it capability to form a partly covalent bond involving charge transfer. Such behavior is investigated by means of several quantum chemical interpretative methods encompasing the topological analysis of the Electron Localization Function (ELF) and Bader’s Quantum Theory of Atoms in Molecules (QTAIM) and two energy decomposition analyses (EDA), namely, the Reduced Variational Space (RVS) and Constrained Space Orbital Variations (CSOV) approaches. Further rationalization is performed by computing ELF and QTAIM local properties such as electrostatic distributed moments and local chemical descriptors such as condensed Fukui functions and dual descriptors. These reactivity indexes are computed within the ELF topological analysis in addition to QTAIM offering access to a nonatomic reactivity local index, for example, on lone pairs. We apply this “subvalence” concept to study the cation selectivity in enzymes involved in blood coagulation (GLA domains of three coagulation factors). We show that the calcium ions are clearly able to form partially covalent charge transfer networks between the subdomain of the metal ion and the carboxylate oxygen lone pairs, whereas magnesium does not have such ability. Our analysis also explains the different role of two groups (high affinity and low affinity cation binding sites) present in GLA domains. If the presence of Ca(II) is mandatory in the central “high affinity” region to conserve a proper folding and a charge transfer network, external sites are better stabilized by Mg(II), rather than Ca(II), in agreement with the experiment. The central role of discrete water molecules is also discussed in order to understand the stabilities of the observed X-ray structures of the GLA domain. Indeed, the presence of explicit water molecules generating indirect cation-protein interactions through water networks is shown to be able to reverse the observed electronic selectivity occurring when cations directly interact with the Gla domain without the need of water. J. Chem. Theory Comput. 2010, 6, 1048–1063 1048 10.1021/ct100089s  2010 American Chemical Society Published on Web 03/12/2010