Simulation of interactions between nucleic acid bases by refined atom-atom potential functions

Energy of interaction between nitrogen bases of nucleic acid has been calculated as a function of parameters determining the mutual position of two bases. Refined atom-atom potential functions are suggested. These functions contain terms proportional to the first (electrostatics), sixth (or tenth for the atoms forming a hydrogen bond) and twelfth (repulsion of all atoms) powers of interatomic distance. Calculations have shown that there are two groups of minima of the base interaction energy. The minima of the first group correspond to coplanar arrangement of the base pairs and hydrogen bond formation. The minima of the second group correspond to the position of bases one above the other in almost parallel planes. There are 28 energy minima corresponding to the formation of coplanar pairs with two (three for the G:C pair) almost linear N-H . . . O and (or) N-H . . . N hydrogen bonds. The position of nitrogen bases paired by two such H-bonds in any crystal of nucleic acid component in polynucleotide complexes and in tRNA is close to the position in one of these minima. Besides, for each pair there are energy minima corresponding to the formation of a single N-H . . . O or N-H . . . N and one C-H . . . O or C-H . . . N hydrogen bond. The form of potential surface in the vicinity of minima has been characterized. The results of calculations agree with the experimental data and with more rigorous calculations based on quantum-mechanical approach.     

Beyond nucleic acid base pairs: from triads to heptads

Hydrogen-bonded base pairs are an important determinant of nucleic acid structure and function. However, other interactions such as base-base stacking, base-backbone, and backbone-backbone interactions as well as effects exerted by the solvent and by metal or NH(4)(+) ions also have to be taken into account. In addition, hydrogen-bonded base complexes involving more than two bases can occur. With the rapidly increasing number and structural diversity of nucleic acid structures known at atomic detail higher-order hydrogen-bonded base complexes, base polyads, have attracted much interest. This review provides an overview on the occurrence of base polyads in nucleic acid structures and describes computational studies on these nucleic acid building blocks.     

Hydration of nucleic acid bases studied using novel atom-atom potential functions

New simple atom-atom potential functions for simulating behavior of nucleic acids and their fragments in aqueous solutions are suggested. These functions contains terms which are inversely proportional to the first (electrostatics), sixth (or tenth for the atoms, forming hydrogen bonds) and twelfth (repulsion of all the atoms) powers of interatomic distance. For the refinement of the potential function parameters calculations of ice lattice energy, potential energy and configuration of small clusters consisting of water and nucleic acid base molecules as well as Monte Carlo simulation of liquid water were performed. Calculations using new potential functions give rise to more linear hydrogen bonds between water and base molecules than using other potentials. Sites of preferential hydration of five nucleic bases - uracil, thymine, cytosine, guanine and adenine as well as of 6,6,9-trimethyladenine were found. In the most energetically favourable sites water molecular interacts with two adjacent hydrophilic centres of the base. Studies of interaction of the bases with several water molecules showed that water-water interactions play an important role in the arrangement of the nearest to the base water molecules. Hydrophilic centres are connected by "bridges" formed by hydrogen bonded water molecules. The results obtained are consistent with crystallographic and mass-spectrometric data.     

Simulation of Interactions between Nucleic Acid Bases by Refined Atom-Atom Potential Functions

Abstract

Energy of interaction between nitrogen bases of nucleic acids has been calculated as a function of parameters determining the mutual position of two bases. Refined atom-atom potential functions are suggested. These functions contain terms proportional to the first (electrostatics), sixth (or tenth for the atoms forming a hydrogen bond) and twelfth (repulsion of all atoms) powers of interatomic distance. Calculations have shown that there are two groups of minima of the base interaction energy. The minima of the first group correspond to coplanar arrangement of the base pairs and hydrogen bond formation. The minima of the second group correspond to the position of bases one above the other in almost parallel planes. There are 28 energy minima corresponding to the formation of coplanar pairs with two (three for the G:C pair) almost linear N-H … O and (or) N-H … N hydrogen bonds. The position of nitrogen bases paired by two such H-bonds in any crystal of nucleic acid component, in polynucleotide complexes and in tRNA is close to the position in one of these minima. Besides, for each pair there are energy minima corresponding to the formation of a single N-H … O or N-H … N and one C-H … O or C-H … N hydrogen bond. The form of potential surface in the vicinity of minima has been characterized. The results of calculations agree with the experimental data and with more rigorous calculations based on quantum- mechanical approach.     

Molecular basis of chromosome banding

Silver and mercury ions are known to react with the bases of nucleic acids in solution. At low cation/base ratios Ag+ has an affinity for GC pairs in DNA, whereas Hg++ is preferentially bound to AT-rich nucleic acids. We have used fluorometry to measure the effect of these cations on the fluorescence intensity of preformed complexes of acranil and DNA in solution. The results are: 1) Ag+ enhances the fluorescence intensity presumably by affecting the dye intercalated in the vicinity of GC-pairs. 2) The addition of Hg++ leads to a quenching of the fluorescence intensity of the complex at low ion/base ratios, suggesting an effect on the dye molecules bound to AT pairs. At high GC-content of the nucleic acid, slight enhancement of the fluorescence intensity occurs with Hg++. 3) With both metals there is a correlation between base content of DNA and effect on the intensity of fluorescence indicating base specificity of the dye-polymer interaction.     

The effect of cross-links on the conformational dynamics of duplex DNA.

The base pair lifetimes and apparent dissociation constants of a 21 base DNA hairpin and an analog possessing a disulfide cross-link bridging the 3'- and 5'-terminal bases were determined by measuring imino proton exchange rates as a function of exchange catalyst concentration and temperature. A comparison of the lifetimes and apparent dissociation constants for corresponding base pairs of the two hairpins indicates that the cross-link neither increases the number of base pairs involved in fraying nor alters the lifetime, dissociation constant, or the opened structure from which exchange occurs for the base pairs that are not frayed. The cross-link does, however, stabilize the frayed penultimate base pair of the stem duplex. Significantly, it appears that the disulfide cross-link is more effective at preventing fraying of the penultimate base pair than is the 5 base hairpin loop. Because this disulfide cross-link can be incorporated site specifically, and does not adversely affect static or dynamic properties of DNA, it should prove very useful in studies of nucleic acid structure and function.     

The thermodynamic effects of exposing nucleic acid bases to water: solubility measurements in water and organic solvents

In order to examine the thermodynamic effects of exposing nucleic acid bases to water, we have measured the solubility of adenine, cytosine, and uracil in water and in organic solvents as a function of temperature. Transfer of a nucleic acid base from an organic environment into water is characterized by positive values for ΔH and for ΔS. We conclude from this result that the overall interaction between nucleic acid bases and water cannot be hydrophobic. If the effect we observe represents structure breaking in water by nucleic acid bases, this process would account for a major portion of the large, positive melting entropy of DNA, and would also contribute substantially to the melting enthalpy.     

Enlarged Similarity of Nucleic Acid Sequences

The concept of nucleic acid sequence base alternations is presented.The number of base alterations for the sequences of differentlength is established. The definition of "enlarged similarity"of nucleic acids sequences on the basis of sequence base alterationsis introduced. Mutual information between sequences is usedas a quantitative measure of enlarged similarity for two comparedsequences. The method of mutual information calculation is developedconsidering the correlation of bases in compared sequences.The definitions of correlated similarity and evolution similaritybetween compared sequences are given. Results of the use ofenlarged similarity approach for DNA sequences analysis arediscussed.     

Overview of nucleic acid analysis programs

We outline the mathematical distinctions among seven of the most popular computer programs currently used to analyze the spatial arrangements of bases and base pairs in nucleic acid helical structures. The schemes fall into three basic categories on the basis of their definitions of rotational parameters: matrix-based, projection-based, and combined matrix- and projection-based. The approaches also define and construct base and base-pair coordinate frames in a variety of ways. Despite these mathematical distinctions, the computed parameters from some programs are strongly correlated and directly comparable. By contrast, other programs which use identical methodologies sometimes yield very different results. The choice of reference frame rather than the mathematical formulation has the greater effect on calculated parameters. Any factor which influences the reference frame, such as fitting or not fitting standard bases to the experimentally derived coordinates, will have a noticeable effect on both complementary base pair and dimer step parameters.     

Theoretical studies on protein-nucleic acid interactions. II. Hydrogen bonding of amino acid side chains with bases and base pairs of nucleic acids

With a view to understanding the role of hydrogen bonds in the recognition of nucleic acids by proteins, hydrogen bonding between the bases and base pairs of nucleic acids and the amino acids (Asn, Gln, Asp and Glu, and charged residues Arg⁺, Glu^?, and Asp^?) has been studied by a second-order perturbation theory. Binding energies have been calculated for all possible configurations involving a pair of hydrogen bonds between the base (or base pair) and the amino acid residue. Our results show that the hydrogen bonding in these cases has a large contribution from electrostatic interaction. In general, the charged amino acids, compared to the uncharged ones, form more stable complexes with bases or base pairs. The hydrogen-bond energies are an order of magnitude smaller than the Coulombic interaction energies between basic amino acids (Lys⁺, Arg⁺, and His⁺) and the phosphate groups of nucleic acids. The stabilities of the complexes of amino acids Asn, Gln, Asp, and Glu with bases are in the order: G–X > C–X > A–X U–X or T–X, and G · C–X > A · T(U)–X, where X is one of these amino acid residues. It has been shown that Glu^? and Asp^? can recognize guanine in single-stranded nucleic acids; Arg⁺ can recognize G · C base pairs from A · T base pairs in double-stranded structures.     

Hybrid simulation approach incorporating microscopic interaction along with rigid body degrees of freedom for stacking between base pairs

Stacking interaction between the aromatic heterocyclic bases plays an important role in the double helical structures of nucleic acids. Considering the base as rigid body, there are total of 18 degrees of freedom of a dinucleotide step. Some of these parameters show sequence preferences, indicating that the detailed atomic interactions are important in the stacking. Large variants of non‐canonical base pairs have been seen in the crystallographic structures of RNA. However, their stacking preferences are not thoroughly deciphered yet from experimental results. The current theoretical approaches use either the rigid body degrees of freedom where the atomic information are lost or computationally expensive all atom simulations. We have used a hybrid simulation approach incorporating Monte‐Carlo Metropolis sampling in the hyperspace of 18 stacking parameters where the interaction energies using AMBER‐parm99bsc0 and CHARMM‐36 force‐fields were calculated from atomic positions. We have also performed stacking energy calculations for structures from Monte‐Carlo ensemble by Dispersion corrected density functional theory. The available experimental data with Watson–Crick base pairs are compared to establish the validity of the method. Stacking interaction involving A:U and G:C base pairs with non‐canonical G:U base pairs also were calculated and showed that these structures were also sequence dependent. This approach could be useful to generate multiscale modeling of nucleic acids in terms of coarse‐grained parameters where the atomic interactions are preserved. This method would also be useful to predict structure and dynamics of different base pair steps containing non Watson–Crick base pairs, as found often in the non‐coding RNA structures. © 2015 Wiley Periodicals, Inc. Biopolymers 105: 212–226, 2016.     

Simulation of interactions in the co-planar nucleic acid base pairs using atom-atom potential functions

Calculations of the energy of nucleic acid base interactions as a function of parameters determining mutual position of two bases in a plane have been performed. Atom-atom potential functions used include terms proportional to the first (electrostatic), sixth (or tenth for the atoms of hydrogen bond) and 12th power of interatomic distance. The calculations have shown the existence of 27 energy minima which correspond to the formation of co-planar pairs with two (or three for G : C pair) almost linear N--H...O and N--H...N hydrogen bonds. The positions of nitrogen bases bound by two hydrogen bonds in every crystal of nucleic acid components, in the complexes of polynucleotides and in tRNA are near to the positions in one of these minima. In addition for every pair there exist energy minima which correspond to the formation of one N--H...O or N--H...N and one C--H...O or C--H...N hydrogen bond. Energy behavior near minima have been investigated. The results of our calculations are in agreement with experimental data and with the calculations which employ quantum mechanical results.     

Nitrogen-15 chemical shifts in AT (adenine-thymine) and CG (cytosine-guanine) nucleic acid base pairs

This paper presents ab initio (DFT) calculations of the 15N chemical shifts in AT (Adenine-Thymine) and CG (Cytosine-Guanine) nucleic acid base pairs. Calculations were done on 14 AT and 18 CG base pairs using experimental (X-ray) geometries obtained from several DNA decamers. The calculated chemical shifts are compared with the experimental values in the pure bases and subjected to statistical analysis to explore their sensitivity to the local geometry and pair helix parameters. The results indicate that the 15N chemical shifts, isotropic and principal components are quite sensitive to small changes in the geometry of the pairs, but they do not correlate well with the helix pair parameters. From the statistical analysis, several linear correlations between structural parameters and chemical shifts emerge. These relationships may serve as a foundation to extract information on molecular structure from 15N chemical shift measurements.     

Isostericity and tautomerism of base pairs in nucleic acids

The natural bases of nucleic acids form a great variety of base pairs with at least two hydrogen bonds between them. They are classified in twelve main families, with the Watson–Crick family being one of them. In a given family, some of the base pairs are isosteric between them, meaning that the positions and the distances between the C1′ carbon atoms are very similar. The isostericity of Watson–Crick pairs between the complementary bases forms the basis of RNA helices and of the resulting RNA secondary structure. Several defined suites of non-Watson–Crick base pairs assemble into RNA modules that form recurrent, rather regular, building blocks of the tertiary architecture of folded RNAs. RNA modules are intrinsic to RNA architecture are therefore disconnected from a biological function specifically attached to a RNA sequence. RNA modules occur in all kingdoms of life and in structured RNAs with diverse functions. Because of chemical and geometrical constraints, isostericity between non-Watson–Crick pairs is restricted and this leads to higher sequence conservation in RNA modules with, consequently, greater difficulties in extracting 3D information from sequence analysis. Nucleic acid helices have to be recognised in several biological processes like replication or translational decoding. In polymerases and the ribosomal decoding site, the recognition occurs on the minor groove sides of the helical fragments. With the use of alternative conformations, protonated or tautomeric forms of the bases, some base pairs with Watson–Crick-like geometries can form and be stabilized. Several of these pairs with Watson–Crick-like geometries extend the concept of isostericity beyond the number of isosteric pairs formed between complementary bases. These observations set therefore limits and constraints to geometric selection in molecular recognition of complementary Watson–Crick pairs for fidelity in replication and translation processes.     

Interactions between nucleic acid bases. New parameters of potential functions and energy minima

The parameters of atom-atom potential functions suggested by one of the authors in 1979-1986 were slightly changed. The changes were performed to achieve a better agreement with experimental data of interaction energy values in global minima and hydrogen bond lengths. These changes resulted in better accord with experimental values of distances between the layers in DNA monomer crystals and between the base pairs in oligonucleotide duplexes. The refined potential functions were used to calculate the energy of interactions between nucleic acid bases in various mutual positions. The calculations revealed a few types of mutual base arrangements in minima of interaction energy for each pairwise base combination. A new type of minima was found, which correspond to a nearly perpendicular arrangement of base rings and the formation of the intermolecular hydrogen bond.     

Effect of protonation of nucleic acid bases on the energy of formation of the Watson-Crick pairs

Neutral and protonated nucleic bases and their complexes were calculated using a modified MNDO method. On the basis of the obtained proton affinities we conclude that proton transfer from positively charged amino acid residues to nucleic bases is quite possible. The protonation influence upon the structure and the energy of complementary base pairs was studied. The protonation of guanine is shown to stabilize the GC complex, but the protonation of cytosine destabilizes it. The energy of the AU pair increases upon protonation of adenine due to ion--dipole interactions. The protonation of uracil leads to a proton transfer between the bases and to the stabilization of the AU pair.