Understanding selectivity of hard and soft metal cations within biological systems using the subvalence concept. I. Application to blood coagulation: direct cation-protein electronic effects vs. indirect interactions through water networks.
Understanding selectivity of hard and soft metal cations within biological systems using the subvalence concept. I. Application to blood coagulation: direct cation-protein electronic effects vs. indirect interactions through water networks.
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DOI：
10.1021/ct100089s
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发表时间：
2010-03-12
影响因子：
5.5
通讯作者：
Piquemal, J. -P.
中科院分区：
文献类型：
--
作者：
de Courcy, B.;Pedersen, L. G.;Parisel, O.;Gresh, N.;Silvi, B.;Pilme, J.;Piquemal, J. -P.
根据de Courcy等人（（2009）Intercep.2009）的先前研究，Sci. Comput. Life Sci. 1，55-60），我们证明了在这方面的贡献，使用量子化学，金属阳离子表现出特定的拓扑特征，在其密度与配体相互作用的电子局域化根据其“软”或“硬”的字符。引入金属阳离子的次价概念，我们表明，金属阳离子可以分裂其外壳密度（所谓的次价域或盆地），根据它的能力，形成一个部分共价键，涉及电荷转移。这种行为是通过几个量子化学的解释方法，包括拓扑分析的电子局域化函数（ELF）和巴德的量子理论的原子在分子中（QTAIM）和两个能量分解分析（EDA），即限制变分空间（RVS）和约束空间轨道变化（CSOV）的方法。进一步合理化是通过计算ELF和QTAIM局部属性，如静电分布的时刻和局部化学描述符，如凝聚福井功能和双描述符。这些反应性指数是在ELF拓扑分析中计算的，除了QTAIM提供非原子反应性局部指数，例如孤对。我们应用这个“亚价”的概念来研究参与血液凝固的酶（三种凝血因子的GLA结构域）的阳离子选择性。我们表明，钙离子显然能够形成部分共价电荷转移网络之间的子域的金属离子和羧酸盐氧孤对，而镁没有这样的能力。我们的分析还解释了GLA结构域中存在的两组（高亲和力和低亲和力阳离子结合位点）的不同作用。如果Ca（II）的存在是强制性的，在中心的“高亲和力”区域，以保存适当的折叠和电荷转移网络，外部网站更好地稳定Mg（II），而不是Ca（II），与实验一致。离散的水分子的中心作用也进行了讨论，以了解所观察到的Gla域的X射线结构的稳定性。事实上，通过水网络产生间接阳离子-蛋白质相互作用的明确水分子的存在被证明能够逆转当阳离子直接与Gla结构域相互作用而不需要水时所观察到的电子选择性。
Following a previous study by de Courcy et al. ((2009) Interdiscip. Sci. Comput. Life Sci. 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 its “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 behaviour 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 Restricted 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 non atomic 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 stabilised by Mg(II), rather than Ca(II), in agreement with experiment. The central role of discrete water molecules is also discussed in order to understand the stabilities of the observed X-rays 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 occuring when cations directly interact with the Gla domain without the need of water.
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