Predicting the coordination geometry for Mg2+ in the p53 DNA-binding domain: insights from computational studies

Zn(2+) in the tumor-suppressor protein p53 DNA-binding domain (DBD) is essential for its structural stability and DNA-binding specificity. Mg(2+) has also been recently reported to bind to the p53DBD and influence its DNA-binding activity. In this contribution, the binding geometry of Mg(2+) in the p53DBD and the mechanism of how Mg(2+) affects its DNA-binding activity were investigated using density functional theory (DFT) calculations and molecular dynamics (MD) simulations. Various possible coordination geometries of Mg(2+) binding to histidines (His), cysteines (Cys), and water molecules were studied at the B3LYP/6-311+g** level of theory. The protonation state of Cys and the environment were taken into account to explore the factors governing the coordination geometry. The free energy of the reaction to form the Mg(2+) complexes was estimated, suggesting that the favorable binding mode changes from a four- to six-coordinated geometry as the number of the protonated Cys increases. Furthermore, MD simulations were employed to explore the binding modes of Mg(2+) in the active site of the p53DBD. The simulation results of the Mg(2+) system and the native Zn(2+) system show that the binding affinity of Mg(2+)to the p53DBD is weaker than that of Zn(2+), in agreement with the DFT calculation results and experiments. In addition, the two metal ions are found to make a significant contribution to maintain a favorable orientation for Arg248 to interact with putative DNA, which is critically important to the sequence-specific DNA-binding activity of the p53DBD. However, the effect of Mg(2+) is less marked. Additionally, analysis of the natural bond orbital (NBO) charge transfer reveals that Mg(2+) has a higher net positive charge than Zn(2+), leading to a stronger electrostatic attractive interaction between Mg(2+) and putative DNA. This may partly explain the higher sequence-independent DNA-binding affinity of p53DBD-Mg(2+) compared to p53DBD-Zn(2+) observed in experiment.     

Potential energy surface and rovibrational calculations for the Mg+-H2 and Mg+-D2 complexes

A three-dimensional potential energy surface is developed to describe the structure and dynamical behavior of the Mg(+)-H(2) and Mg(+)-D(2) complexes. Ab initio points calculated using the RCCSD(T) method and aug-cc-pVQZ basis set (augmented by bond functions) are fitted using a reproducing kernel Hilbert space method [Ho and Rabitz, J. Chem. Phys. 104, 2584 (1996)] to generate an analytical representation of the potential energy surface. The calculations confirm that Mg(+)-H(2) and Mg(+)-D(2) essentially consist of a Mg(+) atomic cation attached, respectively, to a moderately perturbed H(2) or D(2) molecule in a T-shaped configuration with an intermolecular separation of 2.62 A? and a well depth of D(e) = 842 cm(-1). The barrier for internal rotation through the linear configuration is 689 cm(-1). Interaction with the Mg(+) ion is predicted to increase the H(2) molecule's bond-length by 0.008 A?. Variational rovibrational energy level calculations using the new potential energy surface predict a dissociation energy of 614 cm(-1) for Mg(+)-H(2) and 716 cm(-1) for Mg(+)-D(2). The H-H and D-D stretch band centers are predicted to occur at 4059.4 and 2929.2 cm(-1), respectively, overestimating measured values by 3.9 and 2.6 cm(-1). For Mg(+)-H(2) and Mg(+)-D(2), the experimental B and C rotational constants exceed the calculated values by ～1.3%, suggesting that the calculated potential energy surface slightly overestimates the intermolecular separation. An ab initio dipole moment function is used to simulate the infrared spectra of both complexes.     

Transition-metal complexes of boron-new insights and novel coordination modes

Since the publication of the last review in 1998, the transition-metal chemistry of boron has continued to raise unceasing interest. Boryl complexes, representing the most extensive subclass, have remained a focus of intense research, particularly for their implication in the metal-mediated functionalization of organic substrates. Absolute novelties such as borane complexes and terminal borylene complexes have been structurally authenticated. Upon further elaboration of these compounds, the known coordination modes of boron-based ligands have grown considerably. Combined structural and theoretical investigations have contributed to elucidate the fundamental electronic characteristics of the transition-metal-boron bond and are leading to applications of these compounds. The most useful synthetic strategies for the generation of transition-metal-boron bonds are highlighted here, and the most recent and intriguing compounds that have been reported are outlined and discussed.     

Experimental and computational studies of intracomplex reactions in Mg+(primary, secondary alkylamine) complexes induced by photoexcitation of Mg+

We report herein a comprehensive study of photoinduced reactions in complexes of Mg+ with primary (n-propyl- and isopropylamine) and secondary amines (dipropyl- and diisopropylamine) in the spectral range of 230-440 nm. Similar to the methyl- and ethylamine complexes studied previously, N-H bond activation of these complexes is very unfavorable. Instead, the C(alpha)-C, C-N, and C(alpha)-H bond-cleavage photoproducts are observed after photoexcitation of the Mg+ complexes (3(2)P<--3(2)S). For Mg+(primary amine) complexes, for example, Mg+-NH2CH2CH2CH3, and Mg+-NH2CH(CH3)2, the photoproducts resulting from C(alpha)--C rupture prevail after P(z) and charge-transfer excitations, whereas the Mg+ photofragment is predominant upon P(x,y) excitation. However, with further N-alkyl substitution, as in Mg+(secondary amine) complexes, for example, Mg+-NH(CH2CH2CH3)2 and Mg+-NH[CH(CH3)2]2, a novel intracomplex C-C coupling photoreaction dominates on P(x,y) excitation of Mg+, which is believed to arise from Mg+* insertion into the C-N bond. With P(z) and charge-transfer excitation, the Mg-R elimination photoproducts, arising from C(alpha)-C bond cleavage, predominate. The energetics and possible mechanisms of the intracomplex photoreactions are analyzed in detail with the help of extensive quantum mechanics calculations.     

First principles study and database analyses of structural preferences for sodium ion (Na+) solvation and coordination

Extensive computations were performed on aqueous clusters of monovalent sodium cation [Na⁺(H₂O) _n ; (n = 1–20)] using MP2/cc-pVTZ and density functional theory. The structure, energy, and coordination number (CN) preference of a large number of competing conformations of different complexes have been explored. For complexes up to n = 12, the CN 4 is most preferred while 5, 6 CNs are favored in case of larger complexes containing up to 20 water molecules. These results are in very good agreement with experimental observations. The strength of hydrogen bonding among the waters coordinated to the Na⁺ ion is found to play a major role in the stability of the complexes. The varying preferences for CN of Na⁺ ion were explored by screening two important databases: Protein Databank and Cambridge Structural Database. A linear correlation is observed between the M (Metal)–O distance and the charge on metal ion in complex with the increase in CN of metal ion.     

Theoretical study of the complexes of horminone with Mg2+ and Ca2+ ions and their relation with the bacteriostatic activity

The coordination of the horminone molecule with hydrated magnesium and calcium divalent ions was studied by means of the density functional theory. All-electron calculations were performed with the B3LYP/6-31G method. The first layer of the water molecules surrounding the metallic cations was included. It was found that the octahedral [horminone(O(a)-O(d))-Mg-(H(2)O)(4)](2+) complex is more stable than [Mg(H(2)O)(6)](2+). That is, horminone is able to displace two water units from the hexahydrated complex. This behavior does not occur for Ca(2+). Consistently, [horminone(O(a)-O(d))-Mg-(H(2)O)(4)](2+) has a greater metal-ligand binding energy than [horminone(O(a)-O(d))-Ca-(H(2)O)(4)](2+). The preference of horminone by Mg(2+) is enlightened by these results. Moreover, its electronic structure, as shown by huge changes in the atomic populations, is strongly perturbed by Mg(2+). Indeed, horminone, bonded to [Mg(H(2)O)(4)](2+), is able to cross the bacterial membrane cell. Once inside, [horminone(O(a)-O(d))-Mg-(H(2)O)(4)](2+) binds to rRNA phosphate groups yielding [horminone(O(a)-O(d))-Mg-(H(2)O)(PO(4)H(2))(PO(4)H(3))(2)](+). These results give insights into how horminone may inhibit the initial steps of protein synthesis. The stability of the studied systems is accounted for in terms of the calculated structural and electronic properties: Mg-O and Ca-O bond lengths, charge transfers, and binding energies.     

Comparative studies of the photoinduced reactions in the Mg+-SCNC2H5 and Mg+-NCSC2H5 complexes

The photoinduced reactions of the complexes Mg+-SCNC2H5 and Mg+-NCSC2H5 are studied comparatively in the spectral range of 230-440 nm. One-photon excitation of the complexes through the Mg+ chromophore (3 2P <-- 3 2S) gives rise to the evaporative fragment as well as the molecular activation and charge transfer products. The action spectra of the complexes consist of three broad peaks for Mg+-SCNC2H5 and two for Mg+-NCSC2H5, which accord with the structures obtained from quantum mechanics calculations. These calculations reveal two association isomers for Mg+-SCNC2H5: one is with Mg+ being linked to the S atom and the other to the N atom. The former is more stable than the latter by only 0.23 eV. Both of the isomers have been shown to exist in the complex source employed in our experiments. On the other hand, only one stable structure is found for the complex Mg+-NCSC2H5 characterized by the Mg+-N linkage. In general, the photofragments are dominated by Mg+ at lambda > 400 nm, which decreases with decreasing wavelength accompanied by the increase in other photoproducts. In addition, the branching ratios of Mg+ to other photoproducts are nearly constant in the short wavelength region but decrease with decreasing wavelength. The observed photoreactions have been reasonably explained.     

Dimethylplatinum(II) complexes: computational insights into Pt-C bond protonolysis

A detailed density functional theory (DFT) study of the protonation and subsequent methane elimination reactions of dimethylplatinum(II) complexes in presence of triflic acid in various solvents has been undertaken to contribute to the debate concerning the mechanism of the electrophilic cleavage of the Pt-C bond in Pt(II) complexes. Both mechanisms of direct one-step proton attack at the Pt-C bond (S(E)2) and stepwise oxidative-addition on the central metal followed by reductive elimination (S(E)(ox)) have been explored for a series of dimethylplatinum(II) complexes changing the nature of the ancillary ligands and the solvent. Theoretical calculations show that the most likely mechanism cannot be predicted on the basis of spectator ligands donating properties only. A one-step protonolysis pathway is characteristic for complexes containing P based ligands, whereas for complexes containing N based and, in general, hard poor-donor ligands a common behavior cannot be indicated. Solvent nucleophilicity can influence the rate of the S(E)(ox) rate mechanism, whereas its steric hindrance can induce a change of the preferred mechanism. The hypothesis that five-coordinate methyl hydrido platinum(IV) intermediates might be formed along the S(E)(ox) pathway is not supported. Only six-coordinate Pt(IV) hydride complexes are calculated to be stable intermediates generated by direct protonation at the platinum center. Formation and experimental detection of six-coordinate Pt(IV) hydrides, nevertheless, cannot be considered a definite evidence that a S(E)(ox) mechanism is operative because such intermediates can be also generated by a hydrogen migration to Pt from the carbon atom of the σ-complex methane molecule formed by a S(E)2 attack. For all the examined complexes methane loss occurs by an associative mechanism. Both solvent and anion of the acid can assist methane displacement. Calculations have been also carried out to probe whether the preference for a concerted or a stepwise mechanism should be predicted on the basis of two proposed criteria: metal-complex charge distribution as a consequence of the Pt-C bond polarization and the nature of the highest occupied molecular orbital (HOMO).     

Buckybowls as adsorbents for CO2, CH4, and C2H2: Binding and structural insights from computational study

Noncovalent functionalization of buckybowls sumanene (S), corannulene (R), and coronene (C) with greenhouse gases (GGs) such as CO₂, CH₄ (M), and C₂H₂ (A) has been studied using hybrid density functional theory. The propensity and preferences of these small molecules to interact with the concave and convex surfaces of the buckybowls has been quantitatively estimated. The results indicate that curvature plays a significant role in the adsorption of these small molecules on the π surface and it is observed that buckybowls have higher binding energies (BEs) compared with their planar counterpart coronene. The concave surface of the buckybowl is found to be more feasible for adsorption of small molecules. BEs of small molecules towards π systems is CO₂ > A > M and the BEs of π systems toward small molecules is S > R > C. Obviously, the binding preference is dictated by the way in which various noncovalent interactions, such as π···π, lone pair···π, and CH···π manifest themselves on carbaneous surfaces. To delineate the intricate details of the interactions, we have employed Bader's quantum theory of atoms in molecule and localized molecular orbital energy decomposition analysis (LMO‐EDA). LMO‐EDA, which measures the contribution of various components and traces the physical origin of the interactions, indicates that the complexes are stabilized largely by dispersion interactions. © 2015 Wiley Periodicals, Inc.     

Carbonyl coordination chemistry from a new angle: a computational study of alpha-carbon acidity based on electrophile coordination geometry

[reaction: see text] The dependence of acidity on Li+ coordination geometry to alpha-carbon acids is investigated by generating potential energy surfaces of Li+ complexation with acetaldehyde and its respective enolate. The global minimum for the enolate complex shows significant Li+-pi-system coordination to both oxygen and the alpha-carbon. The gas-phase acidity analysis reveals significantly more alpha-carbon coordination, which presumably enhances the lability of the cleaving proton in the transition state of deprotonation.     

Synthesis and computational studies of Mg complexes supported by 2,2':6,2'-terpyridine ligands

The reactions of the substituted 2,2':6,2'-terpyridine ligands, 4'-mesityl-2,2':6',2'-terpyridine (mesitylterpy) (1a), 4,4',4'-tri-tert-butyl-2,2':6',2'-terpyridine (tri-(t)Buterpy) (1b) and 4'-phenyl-2,2':6',2'-terpyridine (phenylterpy) (1c) with Grignard reagents were investigated. When half an equivalent of mesitylterpy or tri-(t)Buterpy were treated with MeMgBr in diethyl ether, the only products were (R-terpy)MgBr(2) (R = mesityl (5a), or tri-(t)Bu (5b)) and Me(2)Mg and a similar reaction was observed in THF. Compounds 5a and 5b were characterized by X-ray crystallography. Changing the Grignard reagent to PhMgBr also generated 5a and 5b along with Ph(2)Mg, while the reaction between MeMgCl or PhMgCl and 1a or 1b generated (R-terpy)MgCl(2) (R = mesityl (6a), or tri-(t)Bu (6b)) and either Me(2)Mg or Ph(2)Mg, respectively. The products from reactions between phenylterpy (1c) and Grignard reagents were highly insoluble and could not be fully characterized but appeared to be the same as those from reactions with 1a and 1b. In contrast to other studies using tridentate nitrogen ligands, which formed either mixed halide alkyl species or dihalide and bis(alkyl) species depending on whether the Grignard reagent was reacted with the ligand in diethyl ether or THF, the formation of mixed halide, alkyl complexes of the type (R-terpy)MgR'X (R' = Me or Ph; X = Cl or Br) or dialkyl species such as (R-terpy)MgR'(2) (R' = Me or Ph) was not observed here, regardless of the reaction conditions. DFT studies were performed to complement the experimental studies. The experimental results could not be accurately reproduced unless π-stacking effects associated with free terpyridine were included in the model. When these effects were included, the calculations were consistent with the experimental results which indicated that the formation of the terpy Mg dihalide species and R'(2)Mg (R' = Me or Ph) is thermodynamically preferred over the formation of mixed alkyl halide Mg species. This is proposed to be due to the increased steric bulk of the terpy ligand in the coordination plane, compared with other tridentate nitrogen donors.     

A combined computational and experimental study of polynuclear Ru-TPPZ complexes: insight into the electronic and optical properties of coordination polymers

We report a combined experimental and computational study of polynuclear [Ru(n)(TPPZ)(n)(+1)](2)(n)(+) complexes, of interest in the field of photoactive polymers. The complexes with n = 1, 2, 3 and n > 5 have been synthesized and spectroscopically characterized. A red-shift of the visible band maximum from 2.59 to 2.03 eV is observed going from the monomer to the longer oligomeric species (n > 5). To characterize the geometries, electronic structure, and excited states of these complexes, density functional theory (DFT) and time-dependent DFT calculations on the [Ru(n)(TPPZ)(n)(+1)](2)(n)(+) series with n = 1-4 in solution have been performed. The agreement between experimental and calculated spectra is good, both in terms of absorption maximum energies and relative intensities for different values of n. For all the investigated complexes, we assign the main band in the visible region as a metal-to-metal plus ligand charge transfer (MMLCT) transition. The resulting excited states are delocalized throughout the entire complexes, as they originate from a superposition of pi(TPPZ)-t(2g)(Ru) states. The low-energy shoulder of the main visible absorption band, present in the experimental spectra for n > 1, is proposed to arise from spin-forbidden singlet-triplet transitions of similar MMLCT character, consistent with the observed enhancement of this feature in the spectra of the corresponding Os oligomers.     

Role of Mg2+ and Ca2+ in DNA bending: evidence from an ONIOM-based QM-MM study of a DNA fragment

The binding of hydrated Mg2+ and Ca2+ ions with a DNA fragment containing two phosphate groups, three sugar units, and a G.C base pair is modeled in the anion and dianion states using a three-layer ONIOM approach. A monodentate binding mode was the most stable structure observed for both the ions in the anion model. However, the interactions of Mg2+ and Ca2+ with the dianion model of the DNA fragment gave rise to a large structural deformation at the base pair region, leading to the formation of "ring" structures. In both anion and dianion models, Mg2+-bound structures were considerably more stable than the corresponding Ca2+-bound structures. This feature and the formation of ring structures in the dianion models strongly supported the higher coordination power of the Mg2+ toward DNA systems for its compaction. The charge of the DNA fragment appeared to be crucial in deciding the binding strength as well as the binding mechanism of the metal ions. To the best of our knowledge, this is the first theoretical investigation of the interaction of a comparatively larger DNA model system with the biologically important Mg2+ and Ca2+ ions.     

Amine-tetrachloromethane charge transfer complexes: a structural and computational study

Abstract

Amine-tetrachloromethane charge-transfer complexes have recently been shown to be useful intermediates in transition-metal free solar light-assisted organic synthetic chemistry. Of particular promise is the complex of 1,4-diazabicyclo[2.2.2]octane (DABCO) which may serve as a starting point for several potential reactions involving oxidation of organic compounds. Here we disclose the crystal structure of the [DABCO???CCl₄] complex, and computational studies of two possible complex structures in their ground state, as well as in their first singlet and first triplet excited states.     

Moderating the acidity of Pb(II)-water complexes through the coordination of nonaqueous ligands: a computational study

The metal dication Pb(II) is known to promote catalytic cleavage of the sugar-phosphate backbone in tRNA. The mechanism proposed to achieve this step requires that the [Pb(II)OH(-)](+) moiety act as a nucleophile and alter the local acidity of surrounding water molecules. MP2 calculations investigating the effect that nonaqueous bases have on the stability of dihydrated-Pb(II) show that the height and position of the proton-transfer barrier are sensitive to the presence of a single N- or O-coordinating "spectator" ligand and that, with the addition of two ligands coordinated directly to the Pb(II) center, the equilibrium for the hydrolysis reaction can shift to the left, thus making the Pb(II)-hydrate complex more stable than the Pb(II)-hydroxide complex. The calculations reveal a good correlation between the gas-phase basicities of nonaqueous ligands coordinated to the metal center and the barriers to proton transfer in [Pb(H(2)O)(2)](2+). In terms of the Pb(II)-induced hydrolysis of tRNA, these results indicate that the coordination of [Pb(II)-OH(-)](+) to uracil and cytosine in tRNA increases the basicity of the hydroxyl group and promotes nucleophilic attack of H(+).     

Investigation of coordination of Mg(II) cations to 2-pyrimidinyloxy-N-arylbenzylamines by electrospray mass spectrometry: insights for Mg(II) catalyzed Smiles rearrangement reactions

The CH(3)OH solutions of pyrimidinyloxy-N-arylbenzylamines (1-5) in the presence of Mg(II)X(2) salts (X = Cl or ClO(4)) were investigated by electrospray ionization mass spectrometry and tandem mass spectrometry (MS/MS) subsequently, showing that the cationic Mg(II) complexes 1-5·MgX(+) were important active complexes or intermediates for initiating interesting Smiles rearrangement reactions in both the gas and solution phases. By using different MgX(2) salts and selecting a set of reactants with different substitutes, the role of the counter-ion (X(-)) and the structure effect of the reactants on the Mg(II) catalyzed Smiles rearrangement reactions were studied. Moreover, the solvent effect on Mg(II) catalyzed Smiles rearrangement reactions was revealed by studying the CH(3)OH adduct complexes of 1-5·MgCl(+), which showed that the coordination of CH(3)OH to the Mg(II) center in the complexes decreased the reaction tendency. The mechanisms involved in the gas-phase Mg(II) catalyzed Smiles rearrangement reactions were proposed on the basis of MS/MS experiments and theoretical computations, showing some unique chemistries initiated by introducing Mg(II) into the template molecules.