Electron Correlated Ab Initio Study of Amino Group Flexibility for Improvement of Molecular Mechanics Simulations on Nucleic Acid Conformations and Interactions

High level ab initio studies demonstrate substantial conformational flexibility of amino groups of nucleic acid bases. This flexibility is important for biological functions of DNA. Existing force field models of molecular mechanics do not describe this phenomenon due to a lack of quantitative experimental data necessary for an adjustment of empirical parameters. We have performed extensive calculations of nucleic acid bases at the MP2/6-31G(d,p) level of ab initio theory for broad set of amino group configurations. Two-dimensional maps of energy and geometrical characteristics as functions of two amino hydrogen torsions have been constructed. We approximate the maps by polynomial expressions, which can be used in molecular mechanics calculations. Detailed considerations of these maps enable us to propose a method for determination of numerical coefficients in the developed formulae using restricted sets of points obtained via higher-level calculations.     

The nature of intermolecular interactions between aromatic amino acid residues

The nature of intermolecular interactions between aromatic amino acid residues has been investigated by a combination of molecular dynamics and ab initio methods. The potential energy surface of various interacting pairs, including tryptophan, phenilalanine, and tyrosine, was scanned for determining all the relevant local minima by a combined molecular dynamics and conjugate gradient methodology with the AMBER force field. For each of these minima, single-point correlated ab initio calculations of the binding energy were performed. The agreement between empirical force field and ab initio binding energies of the minimum energy structures is excellent. Aromatic-aromatic interactions can be rationalized on the basis of electrostatic and van der Waals interactions, whereas charge transfer or polarization phenomena are small for all intermolecular complexes and, particularly, for stacked structures. Proteins 2002;48:117-125.     

Functional interactions in bacteriorhodopsin: a theoretical analysis of retinal hydrogen bonding with water.

The light-driven proton pump, bacteriorhodopsin (bR) contains a retinal molecule with a Schiff base moiety that can participate in hydrogen-bonding interactions in an internal, water-containing channel. Here we combine quantum chemistry and molecular mechanics techniques to determine the geometries and energetics of retinal Schiff base-water interactions. Ab initio molecular orbital calculations are used to determine potential surfaces for water-Schiff base hydrogen-bonding and to characterize the energetics of rotation of the C-C single bond distal and adjacent to the Schiff base NH group. The ab initio results are combined with semiempirical quantum chemistry calculations to produce a data set used for the parameterization of a molecular mechanics energy function for retinal. Using the molecular mechanics force field the hydrated retinal and associated bR protein environment are energy-minimized and the resulting geometries examined. Two distinct sites are found in which water molecules can have hydrogen-bonding interactions with the Schiff base: one near the NH group of the Schiff base in a polar region directed towards the extracellular side, and the other near a retinal CH group in a relatively nonpolar region, directed towards the cytoplasmic side.     

Contribution of cation-pi interactions to the stability of protein-DNA complexes

Cation-pi interactions between an aromatic ring and a positive charge located above it have proven to be important in protein structures and biomolecule associations. Here, the role of these interactions at the interface of protein-DNA complexes is investigated, by means of ab initio quantum mechanics energy calculations and X-ray structure analyses. Ab initio energy calculations indicate that Na ions and DNA bases can form stable cation-pi complexes, whose binding strength strongly depends on the type of base, on the position of the Na ion, and whether the base is isolated or included in a double-stranded B-DNA. A survey of protein-DNA complex structures using appropriate geometrical criteria revealed cation-pi interactions in 71% of the complexes. More than half of the cation-pi pairs involve arginine residues, about one-third asparagine or glutamine residues that only carry a partial charge, and one-seventh lysine residues. The most frequently observed pair, which is also the most stable as monitored by ab initio energy calculations, is arginine- guanine. Arginine-adenine interactions are also favorable in general, although to a lesser extent, whereas those with thymine and cytosine are not. Our calculations show that the major contribution to cation-pi interactions with DNA bases is of electrostatic nature. These interactions often occur concomitantly with hydrogen bonds with adjacent bases; their strength is estimated to be from three to four times lower than that of hydrogen bonds. Finally, the role of cation-pi interactions in the stability and specificity of protein-DNA complexes is discussed.     

Phosphate shielding under different conditions results in an enhanced DNA duplex stability

Neutralization of charge of the phosphodiester groups in DNA and the significance for transfer of genetic information will be demonstrated. Theoretical models based on proton shielding are elaborated with ab initio level calculations for a Watson-Crick-type dimer. These results are compared with molecular mechanics studies for duplexes of a hexamer with Rp and Sp phosphate-methylated backbones.     

Theoretical study of antagonists and inhibitors of mammalian adenosine deaminase. I. Adenosine and its aza- and deaza-analogs

Aza- and deazaanalogues of adenosine, including their 1-protonated forms (except for that of 1-deazaadenosine), were studied by computer computation to find a relationship between their molecular structures and substrate properties for the mammalian adenosine deaminase. The atomic charge distribution and maps of the electrostatic potential around their van der Waals molecular surface were calculated for these compounds using the ab initio STO-3G method. The conformational studies were carried out by the MM+ method of molecular mechanics. The mechanism that determines the substrate selectivity of mammalian adenosine deaminase is discussed. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2002, vol. 28, no. 4; see also http://www.maik.ru.     

Reproduction of correct electrostatic field by charges and dipoles on a closed surface

A general algorithm based on the Green function theorem has been developed to correctly reproduce electrostatic fields inside a closed space by point charges and point dipoles on the surface surrounding the space. For actual computations, limited numbers of point charges, including charge pairs replacing point dipoles, are enough to approximate the inner fields. As examples, reaction fields were reproduced by the current surface charges and dipoles for the dielectric models, where a monopole, dipole, or quadrupole was individually set at the center in a vacuum sphere surrounded by high dielectric continuum. The potentials due to those reaction fields agree well with the analytical ones. As an application of this method to the analysis of the electronic structure of the active site of a protein, a combination of the continuum dielectric model and ab initio molecular orbital calculation was carried out. Other applications to molecular dynamics and quantum mechanical calculations are also discussed.     

Theoretical study of antagonists and inhibitors of mammalian adenosine deaminase. II. Isomeric aza-deazaanalogues of adenosine

Isomeric aza-deazaanalogues of adenosine and their N1-protonated forms (except for that of 8-aza-1-deazaadenosine) were studied by computer modeling to find a relationship between their molecular structures and the properties as substrates for the mammalian adenosine deaminase. The atomic charge distribution and maps of the electrostatic potential around their van der Waals molecular surface were calculated using the ab initio STO-3G method. The conformational studies were carried out by the MM+ method of molecular mechanics. The previously proposed mechanism of the substrate acceptance in the active site of mammalian adenosine deaminase was refined, and the potential substrate properties were predicted for two previously unstudied adenosine analogues, 5-aza-9-deazaadenosine and 8-aza-3-deazaadenosine.     

The physical basis of nucleic acid base stacking in water

It has been argued that the stacking of adenyl groups in water must be driven primarily by electrostatic interactions, based upon NMR data showing stacking for two adenyl groups joined by a 3-atom linker but not for two naphthyl groups joined by the same linker. In contrast, theoretical work has suggested that adenine stacking is driven primarily by nonelectrostatic forces, and that electrostatic interactions actually produce a net repulsion between adenines stacking in water. The present study provides evidence that the experimental data for the 3-atom-linked bis-adenyl and bis-naphthyl compounds are consistent with the theory indicating that nonelectrostatic interactions drive adenine stacking. First, a theoretical conformational analysis is found to reproduce the observed ranking of the stacking tendencies of the compounds studied experimentally. A geometric analysis identifies two possible reasons, other than stronger electrostatic interactions, why the 3-atom-linked bis-adenyl compounds should stack more than the bis-naphthyl compounds. First, stacked naphthyl groups tend to lie further apart than stacked adenyl groups, based upon both quantum calculations and crystal structures. This may prevent the bis-naphthyl compound from stacking as extensively as the bis-adenyl compound. Second, geometric analysis shows that more stacked conformations are sterically accessible to the bis-adenyl compound than to the bis-naphthyl compound because the linker is attached to the sides of the adenyl groups, but to the ends of the naphthyl groups. Finally, ab initio quantum mechanics calculations and energy decompositions for relevant conformations of adenine and naphthalene dimers support the view that stacking in these compounds is driven primarily by nonelectrostatic interactions. The present analysis illustrates the importance of considering all aspects of a molecular system when interpreting experimental data, and the value of computer models as an adjunct to chemical intuition.     

PHOSPHATE SHIELDING UNDER DIFFERENT CONDITIONS RESULTS IN AN ENHANCED DNA DUPLEX STABILITY

Neutralization of charge of the phosphodiester groups in DNA and the significance for transfer of genetic information will be demonstrated. Theoretical models based on proton shielding are elaborated with ab initio level calculations for a Watson-Crick–type dimer. These results are compared with molecular mechanics studies for duplexes of a hexamer with R_P and S_P phosphate-methylated backbones.     

Monensin A acid complexes as a model of electrogenic transport of sodium cation

New Monensin A acid complexes with water molecule, sodium chloride and sodium perchlorate were obtained and studied by X-ray and (1)H, (13)C NMR and FT-IR methods as well as ab initio calculations. The crystal structure of the complexes indicates the complexation of the water molecule and Na(+) cation in the pseudo-cycle conformation of the Monensin acid molecule stabilised by intramolecular hydrogen bonds. Important for stabilisation of this structure is also the intermolecular hydrogen bonds with water molecule or the coordination bonds with Na(+) cation. It is demonstrated that the counterions forming intermolecular hydrogen bonds with OH groups influence the strength of the intramolecular hydrogen bonds, but they have no influence on the formation of pseudo-cyclic structure. Spectroscopic studies of the complexes in dichloromethane solution have shown that the pseudo-cyclic structure of the compounds is conserved. As follows from the ab initio calculations, the interactions between the Na(+) cation and the electronegative oxygen atoms of Monensin acid totally change the molecular electrostatic potential around the supramolecular Monensin acid-Na(+) cationic complex relative to that of the neutral Monensin acid molecule.     

DNA HOMO as a new landmark for nucleic acid properties. ab initio calculations and experimental mapping.

Of the non-covalent binding forces in DNA-drug or DNA-protein interaction, electrostatic interaction, stacking interaction, hydrogen bonds and hydrophobic effect have been well established. However, only a few HOMO-LUMO interaction in DNA have been reported. We examined the ab initio calculations of B-DNA duplex 5-mers. Based on the calculated results, we investigated the mapping of HOMO experimentally and found that DNA cleavage patterns with Co(II) and BPO (Benzoyl peroxide) were in good agreement with the ab initio calculation results.     

Applications of the Cartesian coordinate tensor transfer technique in the simulations of vibrational circular dichroism spectra of oligonucleotides

The application of the Cartesian coordinate tensor transfer (CCT) technique for simulations of the IR absorption and vibrational circular dichroism (VCD) spectra of relatively large nucleic acid fragments is demonstrated on several case studies. The approach is based on direct ab initio calculations of atomic tensors, determining molecular properties, for relatively small fragments, and subsequent transfer of these tensors to the larger systems in Cartesian coordinates. This procedure enables precise computations of vibrational spectra for large biomolecular systems, currently with up to several thousands of atoms. The versatile ability of the CCT methods is emphasized on the examples of VCD and IR absorption spectra calculations for B- and Z-forms of DNA, single-, double-, and triple-stranded RNA helices and DNA structures with different base content and sequences. The development and recent improvements of the methodology are followed, including utilization of the constrained normal mode optimization (NMO) strategy and combined quantum mechanics and molecular dynamics simulations. Advantages, drawbacks, and recommendations for future improvements of the CCT method as applied to nucleic acid spectra calculations are discussed.     

Calorimetric and computational study of enthalpy of formation of 3,6-dibutanoic-1,2,4,5-tetroxane

A thermochemical a rather simple experimental technique method, is used to determine the enthalpy of the formation of 3,6-dibutanoic-1,2,4,5-tetroxane. The study is complemented with suitable theoretical calculations at the semiempirical and ab initio levels. A particular satisfactory agreement between both ways is found for the ab initio calculation at the 6-311G basis set level. Some possible extensions of the present procedure are pointed out.     

Molecular polarization maps as a tool for studies of intermolecular interactions and chemical reactivity

Maps for the interaction energy of acetone, pyrrole, furan, and pyridine with a positive unitary charge were computed using ab initio techniques, together with their molecular electrostatic potentials at the same points. The difference between the interaction and electrostatic potential maps yielded polarization maps for the molecules. Finally, maps for the interaction with a negative charge were obtained as the difference between the polarization and electrostatic potential maps.The calculations were carried out for three planes, 2 Bohr radii, 4 Bohr radii, and 8 Bohr radii from the plane containing the heavy atoms for all the molecules. At larger distances, the interaction and electrostatic maps resemble each other qualitatively; however, at shorter distances, where the polarization effects are more significant, the differences between the maps are notable.Interaction and polarization maps can be routinely evaluated for medium-sized molecules, and are likely to become an important tool in drug design and chemical reactivity.     

Computational evaluation of intermolecular interactions of a universal base 3-nitropyrrole in stacked dimers and DNA duplexes

The stacking interactions between a universal base of 3-nitropyrrole (3NP) and four canonical nucleobases were studied by means of ab initio molecular orbital calculations. The stabilities of the complexes are comparable to those of the stacked dimers of canonical bases reported previously. The detailed analysis of the interaction energies revealed the importance of the dipole-dipole interaction included in the Hartree-Fock terms to determine the geometry dependence of the stacking energies. It was also clarified that the dispersion energies included in the electron-correlation terms were essential to obtain adequate stabilities. The contribution of the nitro group was evaluated by the comparative studies of pyrrole and 3NP. The increased molecular dipole moment and surface are expected to account for the enhancement of the stability of the stacked dimers containing 3NP. The force field parameters required for calculation of the molecular mechanics of 3NP were obtained for 3NP on the basis of these molecular orbital calculations. The energy-minimized structures obtained by the molecular mechanics calculations of 3NP accorded with those obtained by the molecular orbital calculations described above. A DNA duplex structure containing 3NP-A, 3NP-T, or 3NP-C was calculated by use of these force field parameters. In the case of 3NP-A, the computationally calculated structure was in good agreement with that previously determined by use of (1)H-NMR except for the orientation of the nitro group.     

How does activation loop phosphorylation modulate catalytic activity in the cAMP-dependent protein kinase: a theoretical study

Phosphorylation mediates the function of many proteins and enzymes. In the catalytic subunit of cAMP-dependent protein kinase, phosphorylation of Thr 197 in the activation loop strongly influences its catalytic activity. In order to provide theoretical understanding about this important regulatory process, classical molecular dynamics simulations and ab initio QM/MM calculations have been carried out on the wild-type PKA-Mg(2) ATP-substrate complex and its dephosphorylated mutant, T197A. It was found that pThr 197 not only facilitates the phosphoryl transfer reaction by stabilizing the transition state through electrostatic interactions but also strongly affects its essential protein dynamics as well as the active site conformation.