Dimethyl Phosphate Anion Research Articles

Geometrical and vibrational features of phosphate, phosphorothioate and phosphorodithioate linkages interacting with hydrated cations: A DFT study

The effect of hexahydrated monovalent and divalent cations on the geometrical and vibrational features of dimethyl phosphate, dimethyl phosphorothioate and dimethyl phosphorodithioate anions (simple suitable model compounds representing the anionic moieties of natural and some modified nucleic acids) was studied. For this purpose, density functional theory (DFT) calculations were carried out at the B3LYP/6-31++G* level. Our results indicate that only K + and Mg 2+ prefer to be located in the bisector plane of the PO 2 − angle, whereas Li + and Na + deviate from this plane. Monovalent and divalent cations are slightly deviated from the OPS − bisector plane and are found closer to the free oxygen atom. Moreover, the present calculations have shown that in contrast to the general belief, the g − g − conformer (with respect to the torsion angles defined around the P–O ester bonds) is not always the energetically most favorable. For instance, the g − t conformer presents the lowest energy in the case of dimethyl phosphorothioate. The calculated vibrational wavenumbers obtained for dimethyl phosphate and dimethyl phosphorothioate interacting with hydrated sodium counterion, were compared with those previously recorded by Raman scattering and infrared absorption (IR) in aqueous solutions. It has been evidenced that the use of explicit solvent versus dielectric continuum, considerably improves the agreement between the theoretical and observed characteristic wavenumbers.

Polyionic Charge Density Plays a Key Role in Differential Recognition of Mobile Ions by Biopolymers

We address the question of what are the molecular mechanisms providing discrimination between seemingly similar counterions binding to various biomolecular surfaces. In the case of protein association with Na (+) and K (+) ions, recent works proposed that specificity of carboxylate functional groups interacting with these mobile ions rationalizes the observed ionic discrimination. We probe in this work whether similar arguments may be used to explain higher propensity of Na (+) ions to associate with DNA compared with K (+) ions, which was suggested by our simulations and some experiments. By comparing our extensive molecular dynamics simulations of Na (+) and K (+) distributions around a 16-base-pair DNA oligomer, [(CGAGGTTTAAACCTCG)] 2, with additional simulations where DNA is replaced by a "soup" of monomers (dimethylphosphate anion), we conclude that DNA specificity toward Na (+)/K (+) is not determined by the underlying functional group specificity. Instead, the collective effect of DNA charges drives larger Na (+) association. To gain additional microscopic insights into the mechanisms of specificity on ionic associations in these systems, we carried out energetic analysis of the association between Na (+) and K (+) with chloride and dimethylphosphate anions. The insights gained from our computational work shed light on a number of experiments on electrolyte solutions of monovalent salts and DNA.

Ca2+–dimethylphosphate complex formation: Providing insight into Ca2+‐mediated local dehydration and membrane fusion in cells

Earlier studies using X-ray diffraction, light scattering, photon correlation spectroscopy, and atomic force microscopy, strongly suggest that SNARE-induced membrane fusion in cells proceeds as a result of calcium bridging opposing bilayers. The bridging of phospholipid heads groups in the opposing bilayers by calcium leads to the release of water from hydrated Ca(2+) ions as well as the loosely coordinated water at PO-lipid head groups. Local dehydration of phospholipid head groups and the calcium, bridging opposing bilayers, then leads to destabilization of the lipid bilayers and membrane fusion. This hypothesis was tested in the current study by atomistic molecular dynamic simulations in the isobaric-isothermal ensemble using hydrated dimethylphosphate anions (DMP(-)) and calcium cations. Results from the study demonstrate, formation of DMP-Ca(2+) complexes and the consequent removal of water, supporting the hypothesis. Our study further demonstrates that as a result of Ca(2+)-DMP self-assembly, the distance between anionic oxygens between the two DMP molecules is reduced to 2.92A, which is in close agreement with the 2.8A SNARE-induced apposition established between opposing bilayers, reported earlier from X-ray diffraction measurements.

Binding of Antitumor Ruthenium Complexes to DNA and Proteins: A Theoretical Approach

The thermodynamics of the binding of the antitumor ammine, amine, and immine complexes of ruthenium(II) and ruthenium(III) to DNA and peptides was studied computationally using model molecules. We performed density functional calculations on several monofunctional ruthenium complexes of the formula [Ru(NH3)5B]z+, where B is an adenine, guanine, or cytosine nucleobase or an 4-methylimidazole, a dimethylthioether, or a dimethylphosphate anion and z = 2 and 3. The pentammineruthenium fragment has been intensively studied and also constitutes a good model for a wide class of antitumor ammine, amine, and imine complexes of Ru(II) and Ru(III), while the considered bases/ligands have been chosen as models for the main binding sites of DNA, nucleobases, and phosphate backbone and proteins, histidyl, and sulfur-containing residue such as methionine or cysteine. Bond dissociation enthalpies and free energies have been calculated for all the considered metal binding sites both in the gas phase and in solution and allow building a binding affinity order for the considered nucleic acid or protein binding sites. The binding of guanine to some bifunctional complexes, [Ru(NH3)(4)Cl2], [cis-RuCl(2)(bpy)2], and [cis-RuCl(2)(azpy)2], has also been considered to evaluate the effect of a second labile chloro or aquo ligand and more realistic polypyridyl and arylazopyridine ligands.

Poly[[aquatris(μ-dimethyl phosphato-κ2O,O′)bis(μ-dimethyl sulfoxide-κO)(dimethyl sulfoxide-κO)dimanganese(II)] nitrate monohydrate

In the title compound, {[Mn2{(O2P(OCH3)2}3(C2H6SO)3(H2O)]NO3·H2O}n, the octa­hedral MnII ions form a polymeric chain, being bridged by both dimethyl sulfoxide mol­ecules and dimethyl phosphate anions. A network of O—H⋯O hydrogen bonds helps to consolidate the crystal packing.

Crystal structure and molecular stereochemistry of polymeric Cu2(DMP)4(DMSO) as a platform for phosphate diester binding

Treatment of a solution of CuCl2 in dimethyl phosphate (DMP) in an inert solvent under nitrogen atmosphere resulted in a light blue fluorescence powder. Slow evaporation of H2O-DMSO solution of this powder led to the formation of blue-sky crystals of a new polymeric Cu(II) complex, with a unit cell composed of Cu2(DMP)4(DMSO), (1). The crystal and molecular structure of the complex was established crystallographically. Compound (1) crystallizes in the monoclinic space group P21/n with a = 12.8920(11)A, b = 13.1966(11)A, c = 14.7926(13)A, α = 90°, β = 98.943(2)°, γ = 90° and Z = 4. A square pyramidal environment for the metal center is established by coordination of oxygen atoms of four bridging DMP ligands in the basal positions and a tri-centered oxygen atom of DMSO in the apical disposition. The sixth position is also affected by a weak interaction with the sulfur atom of DMSO. The phosphorous atom in the bridging DMP is arranged in a deformed tetrahedron with gg conformation for methyl esters with C2v symmetry. Accordingly, the angles of methoxy substituents are unexpectedly smaller than the bridging oxygens, and synchronous z-in and z-out distortions are suggested for DMP anion. The oxygen atom of SOCuCu’ fragment derived from DMSO, functions as a tri-centered nuclei lie almost in a trigonal triangle environment. This study helps provide further insights into the binding nature of phosphate esters to the active sites of enzymes, which catalyze phosphoryl transfer reactions. (© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

The time required for water attack at the phosphorus atom of simple phosphodiesters and of DNA

Phosphodiester linkages, including those that join the nucleotides of DNA, are highly resistant to spontaneous hydrolysis. The rate of water attack at the phosphorus atom of phosphodiesters is known only as an upper limit, based on the hydrolysis of the dimethyl phosphate anion. That reaction was found to proceed at least 99% by C-O cleavage, at a rate suggesting an upper limit of 10(-15) s(-1) for P-O cleavage of phosphodiester anions at 25 degrees C. To evaluate the rate enhancement produced by P-O cleaving phosphodiesterases such as staphylococcal nuclease, we decided to establish the actual value of the rate constant for P-O cleavage of a simple phosphodiester anion. In dineopentyl phosphate, C-O cleavage is sterically precluded so that hydrolysis occurs only by P-O cleavage. Measurements at elevated temperatures indicate that the dineopentyl phosphate anion undergoes hydrolysis in water with a t(1/2) of 30,000,000 years at 25 degrees C, furnishing an indication of the resistance of the internucleotide linkages of DNA to water attack at phosphorus. These results imply that staphylococcal nuclease (k(cat) = 95 s(-1)) enhances the rate of phosphodiester hydrolysis by a factor of approximately 10(17). In alkaline solution, thymidylyl-3'-5'-thymidine (TpT) has been reported to decompose 10(5)-fold more rapidly than does dineopentyl phosphate. We find however that TpT and thymidine decompose at similar rates and with similar activation parameters, to a similar set of products, at pH 7 and in 1 M KOH. We infer that the decomposition of TpT is initiated by the breakdown of thymidine, not by phosphodiester hydrolysis.

Theoretical Studies of the Hydroxide-Catalyzed P−O Cleavage Reactions of Neutral Phosphate Triesters and Diesters in Aqueous Solution: Examination of the Changes Induced by H/Me Substitution

DFT calculations and dielectric continuum methods have been employed to map out the lowest activation free-energy profiles for the alkaline hydrolysis of representative phosphate triesters and diesters, including trimethyl phosphate (TMP), dimethyl 4-nitrophenyl phosphate (DMNPP), dimethyl hydrogen phosphate (DMHP), and the dimethyl phosphate anion (DMP-). The reliability of the calculations is supported by the excellent agreement observed between the calculated and the experimentally determined activation enthalpies for phosphate triesters with poor (TMP) and good (DMNPP) leaving groups. The results obtained for the OH- + DMHP and OH- + DMP- reactions are also consistent with all the available experimental information concerning the hydrolysis reaction of dimethyl phosphate anion at pH > 5. By performing geometry optimizations in the dielectric field (epsilon = 78.39), we found that OH- can attack the phosphorus atom of DMHP without capturing its proton only if the O-H bond of DMHP is oriented opposite the attacking OH- group. In these conditions, the rate for OH- attack on DMHP was found to be approximately 10(3)-fold faster than that for OH- attack on TMP. The calculated rate acceleration induced by the phosphoryl proton corresponds to the maximum rate effect expected from kinetic studies. Overall, our calculations performed on the dimethyl phosphate ester predict that, contrary to what is generally observed for RNA and aryl phosphodiesters, the water-promoted P-O cleavage reaction of DNA should dominate the base-catalyzed reaction at pH 7. These results are suggestive that nucleases may be less proficient as catalysts than has recently been suspected.

Zinc Thiolate Complexes of (N,N,S)‐Tridentate Ligands for the Modeling of Thiolate Alkylating Enzymes

AbstractZinc thiolate complexes of three tridentate (N,N,S) ligands were prepared as models for the structure and function of thiolate alkylating zinc enzymes. N‐(2‐Mercaptoisobutyl)(2‐pyridin‐2‐yl‐methyl)amine (L1) forms isobutylthiolate‐bridged dinuclear complexes with ZnN2S3 coordination. N‐(2‐Mercaptoisobutyl)(2‐pyridin‐2‐yl‐ethyl)amine (L2) yields isobutylthiolate‐bridged dinuclear complexes in which the pyridine donor is not coordinated to zinc, resulting in a ZnNS3 coordination. Only N‐(2‐mercaptoisobutyl)(2‐pyridin‐2‐yl‐ethyl)methylamine (L3) forms the desired mononuclear complexes with ZnN2S2 coordination. The latter react with the alkylating agents CH3I and PO(OCH3)3 in a two‐step process. In the first step the isobutylthiolate function is methylated and its position in the ligand sphere of zinc is taken by I– or OPO(OCH3)2–, respectively, and in the second step the additional thiolate ligand is methylated and replaced by a second iodide or dimethyl phosphate anion. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Computational study of dimethyl phosphate anion and its complexes with water, magnesium, and calcium

AbstractDimethyl phosphate anion (DMP−) is often used to simulate the properties of the phosphate group, an important structural fragment of nucleic acids and phospholipids. Besides its functional importance, DMP− has a strong affinity for metal cations and is often considered to be their binding site. In this study we reevaluate the binding properties of DMP− with water molecules and with explicitly hydrated magnesium and calcium cations in the presence of a polar continuum solvent. We analyze the stability of the DMP− in different conformations that represent possible inner‐ and outer‐sphere binding modes. Our previous work (Petrov et al. J Phys Chem B 2004) has shown that electrostatic calculations, particularly those using a point‐charge model, are wholly inadequate for this purpose. Calculations were performed at the B3LYP/6‐31G(d,p) level of theory within the framework of the COSMO polarized continuum model (CPCM). Our data indicate that magnesium prefers outer‐sphere coordination with DMP−, whereas calcium binds directly. The effect of cation binding on vibrational infrared and Raman spectra are also discussed. We found that the inclusion of polar solvent in the computations improves the agreement between calculated spectral data and experimental results. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2005

Theoretical method for full ab initio calculation of DNA/RNA-ligand interaction energy.

In this paper, we further develop the molecular fractionation with conjugate caps (MFCC) scheme for quantum mechanical computation of DNA-ligand interaction energy. We study three oligonuclear acid interaction systems: dinucleotide dCG/water, trinucleotide dCGT/water, and a Watson-Crick paired DNA segment, dCGT/dGCA. Using the basic MFCC approach, the nucleotide chains are cut at each phosphate group and a pair of conjugate caps (concaps) are inserted. Five cap molecules have been tested among which the dimethyl phosphate anion is proposed to be the standard concap for application. For each system, one-dimensional interaction potential curves are computed using the MFCC method and the calculated interaction energies are found to be in excellent agreement with corresponding results obtained from the full system ab initio calculations. The current study extends the application of the MFCC method to ab initio calculations for DNA- or RNA-ligand interaction energies.

Structure, Stability and Interaction Studies on Nucleotide Analogue Systems

Most of the biological molecules have a good interaction with water molecules. The hydrogen bonding interactions with the structural analogues of nucleic acid phosphate group namely dimethyl phosphate anion (DMP) and diethyl phosphate anion (DEP) are studied employing the ab initio and density functional theory methods. Inspections have been made to locate the reactive sites for the interactions of isomeric forms of mono, di and tri hydrates of alkyl phosphate anion using the above theories. It reveals, water molecules have a very strong interaction with the phosphate group in both the molecules and their interactions induce the changes in the structural parameters of the PO4 group for both the DMP and DEP anions. The optimized structural parameters, total energy, dipole moment and rotational constants are calculated and are compared with the available experimental values. The chemical hardness and chemical potential for these complexes have been calculated at HF/6-31G* level of theory and discussed the conformational stability of these complexes.

The magnitude of [C-H...O] hydrogen bonding in molecular and supramolecular assemblies.

Ab initio calculations at the MP2/6-311++G** level on model systems (N-methylpyridinium complexes of dimethyl ether and dimethyl phosphate anion) provide quantitative measures of the large stabilization energies that arise from [C-H...O] contacts in charged systems. These attractive interactions control (i) the self-assembly of bipyridinium-based catenanes and rotaxanes in solution, (ii) the self-organization of left-handed Z-DNA with alternating [dC-dG] sequences in the solid state, and (iii) the binding of pyridinium derivatives with single- and double-stranded DNA. Slightly attractive interactions occur between the donor ether and phosphate moieties and a neutral pyridine molecule in the gas phase. Electrostatic potential and solvation calculations demonstrate that [C-H...O] interactions which involve a cationic [C-H] donor are dominated by electrostatic terms.

Conformational dynamics of the dimethyl phosphate anion in solution

The conformational dynamics of the DNA phosphodiester linkage in solution is modeled by performing first principles molecular dynamics simulations of the dimethyl phosphate anion ((CH 3O) 2PO 2 − or DMP −) in water, in the presence of a sodium cation. We observe conformational changes in DMP − in solution, which are related to the approach of the sodium cation to the anionic oxygens of DMP −. These simulations demonstrate that the presence of a counterion may play a significant role in driving the transition between different conformers of DMP −.

Orbital interactions in stable and metastable conformations of the dimethylphosphate anion

Natural bond orbital (NBO) theory has been applied to analyze stereoelectronic preferences of the gg, tg and tt stationary states and two connecting transition states of the dimethylphosphate (DMP −) anion. In going from the compact gg to the extended tt state, the O a–P–O a angle closes as phosphoryl anionic oxygen, P–O a, bonds are weakened by negative hyperconjugation. Phosphoryl ester oxygen, P–O e, bonds are strengthened, however, due to increased π-overreach, largely a result of delocalization of ester oxygen lone pair density. In a ‘closing scissors effect’, contraction of the O e–P–O e angle between these stronger bonds also results, in this case due to the dominance of repulsive forces among the lone pairs. Counterintuitive arrangements in the transition states between gg and tg, and between two equivalent, twisted tt stationary states result, again, from dominant repulsions of oxygen lone pairs. Complexation of DMP − with water, Na +, or Mg +2 ions is accompanied by significant charge transfer to the ligand, thus imparting a degree of covalency to the anion–ligand bond. H-bonds between water and the two O a oxygens lead to delocalization of charge through lone pairs at the docking site of DMP − into σ ∗(O w–H) antibonds. For the ion-pairs, charge is transferred by a similar mechanism into Rydberg orbitals on the cation. Rearrangement of electron density within DMP − in the complexes replenishes losses from O a lone pairs and increases the magnitude of the anomeric effect involving O e lone pairs. NBO theory provides a quantitative description of the complex balance of interactions that dictate the conformational features of this biologically significant molecular functionality.

Electronic Polarization and Hydration of the Dimethyl phosphate Anion: An ab Initio Molecular Dynamics Study

We report a molecular dynamics (MD) simulation study of sodium dimethlyphosphate in aqueous solution. The dimethyl phosphate anion (DMP) is a model compound for the phosphodiester linkage in phospholipids and nucleic acids. We compare results from classical MD simulations based on an empirical force field to an ab initio MD simulation in which the forces are derived from the electronic structure in the framework of density functional theory with the Car−Parrinello approach. We have characterized the molecular and electronic structure of both the DMP anion and its first solvation shell in detail. To analyze the charge distribution in individual molecules, we have used maximally localized Wannier orbitals. The radial and orientational distributions of the water molecules revealed a softening of the structure of the first solvation shell of the DMP anion in the ab initio simulation compared to the force field simulation. The ab initio simulation reveals that both the geometry and the electronic structure of ...

A comparison of the B3LYP and MP2 methods in the calculation of phosphate complexes

Hydrogen-bond complexes of dihydrogen phosphate and dimethyl phosphate anions with orthosilicic acid, water, and ionic complexes with sodium cations are investigated with the density functional (B3LYP/6-31G(d,p) and B3LYP/6-31+G(d,p)) theory and the second-order perturbation (MP2/6-31+G(d,p)) theory. The geometries and IR spectra of the complexes obtained with the B3LYP/6-31+G(d,p) and MP2/6-31+G(d,p) level calculations are found to be very similar. Inclusion of diffuse functions in the basis set significantly improves the reproducibility of the experimental data. The BSSE corrections significantly reduce the differences in stabilization energies obtained at different levels of theory, and as expected are the largest with the least flexible basis set calculations.

Theoretical Study of Complexation of Phosphodiester Linkage with Alkali and Alkaline-Earth Cations

Effects of complexation of dimethyl phosphate anion (DMP-) with countercations Li+, Na+, K+, Mg2+, and Ca2+ on geometry, charge distribution, IR spectra, and conformational changes of DMP- are investigated using DFT calculations. IR spectra alterations caused by conformational change are shown to depend on the ionic strength of a cation and environment.

Conformational simulation of phosphosphingolipids by molecular mechanics

Force field parameters were developed for the phosphodiester linkage and introduced into the molecular mechanics program MM3 to simulate conformational states of phosphosphingolipids. The modified MM3 parameter set was tested with the dimethylphosphate anion and the methylphosphorylcholine zwitterion. The results compare well with established conformational preferences of these important functionalities in lipid head groups. At a dielectric constant of ϵ=4.0, generally taken to represent the electrostatic environment of the membrane surface, the diesterphosphate dihedral angles α2 and α3 are predicted to be primarily +sc, +sc in both species. The outer dihedral angles α4 and α5 of the choline functionality are predominantly ap and ±sc, respectively, in the lowest energy structures. Increase of the dielectric constant reveals an extension of these partially folded structures as might occur under the influence of an aqueous environment. This parameter set was then applied to a phosphorylated dihydroceramide to investigate conformational preferences of the head group with respect to the lipid interface. Three of the most probable conformations are compatible with liquid crystalline, bilayer organizations. These conformations exhibit intramolecular hydrogen bonds involving the NH and OH moieties as donors and an ester and/or anionic phosphate oxygen as acceptors. Features of the Boltzmann-distributed conformations are confirmed by known experimental results from NMR spectroscopy.

Adsorption of the Phosphate Groups on Silica Hydroxyls: An ab Initio Study

Adsorption of the phosphate groups on a silica surface is investigated by ab initio calculations of hydrogen-bond complexes of dihydrogen and dimethyl phosphate anions with orthosilicic acid. It is found that the phosphate groups can form strong hydrogen-bonded complexes with the silanols of the silica surface with stabilization energies of ca. −14 kcal/mol per hydrogen bond. The effect of the coordination of the phosphate species by water, orthosilicic acid, and a sodium cation on the geometry and stability of the -sc/-sc conformation is investigated through consideration of 2-fold axial symmetry complexes. Calculations suggest the reduction of the COPO torsion angle of the -sc/-sc conformation of the phosphodiester backbones upon adsorption of molecules containing these moieties on silica compared to the value of this angle found for phosphates in vacuo and in hydrated forms. Both the polarizing and electron density abstracting abilities of silanols cause electron density redistribution, giving rise to strengthening of the phosphoester P−O bonding, weakening of the phosphinyl PO and ester C−O bonding in adsorbed phosphate moieties. A very strong band at 3300 cm-1 appearing during the phosphate adsorption on the silanol hydroxyls is suggested for use as an indication of this phenomenon.