Facultad de Ciencias Fisico-Matematicas

To approach the quantitative understanding of hydration contribution to the accuracy of nucleic acid biosynthesis, a computer simulation has been performed to study the hydration characteristics for individual atoms of DNA bases and various AT and GC base pairs. Both Watson-Crick pairs and other types of pairs with two hydrogen bonds are considered. Monte Carlo simulation of individual bases demonstrates good concord of calculated hydration energies with experimentally determined hydration enthalpies. Computations for base pairs allow us to account for the experimental fact that formation of such pairs in water solution is disadvantageous. The correlations between hydration indices of hydrophilic atoms and their accessible volumes to hydrogen bonding with water were followed. These correlations will allow us to develop a semi-quantitative method of rapid estimation of hydration changes under DNA conformational transitions and binding to other molecules. The main hydration characteristics of mispairs important for their formation in DNA biosynthesis are discussed. ᭧ Journal of Molecular Structure (Theochem) 493 (1999) 301-308 0166-1280/99/$ -see front matter ᭧

Three systems of potential functions (PF) which are used in simulations of hydration of bioorganic molecules have been compared: Poltev and Malenkov (PM), Weiner and Kollman (WK) (used in the widespread AMBER program), and OPLS (optimized potentials for liquid simulations) of Jorgensen (J). The values of interaction energies of individual water molecules with single molecules of nucleic bases calculatedvia PM potentials are in somewhat better accord with mass spectrometric data than those calculatedvia WK PF. OPLS give much smaller energy values for all compounds considered; therefore they were not used in further computations. Monte Carlo simulation of hydration of 9-methyladenine, 1-methyluracil, and 1-methylthymine in systems with 300 water molecules and periodic boundary conditions have been performed. Simulations with PM potentials give better agreement with the experimental data on hydration energies than those with WK PF that allows to prefer PM PF for simulation of hydration...

Abstract: - Computational results are described of interactions between nucleic acid bases and of searching for local minima of the interaction energy. As the bases are the elementary units of genetic material, their interactions are important for understanding the molecular ...

The results of the Monte Carlo Metropolis simulation of water structure and of the hydration of nucleic acid fragments, complementary base pairs and mispairs, base pair stacks, and duplex fragments have been summarized. Systematic investigations suggest some general conclusions:

The conformational properties of some nucleotide sequences result in their ability to bind specifically some ligands or to be recognized by specific proteins. In order to investigate the dependence of conformational behavior of the DNA duplex on nucleotide sequence, we analyzed the interaction energy of nucleic acid bases as a function of conformational parameters and base sequence. Extended regions of minimum energy values were found for different sequences. Although these regions (valleys) largely overlap, each one shows specificity for a particular sequence. This suggests that a specific pathway of changes in conformational parameters exists for each sequence. The changes may be accompanied by considerable shifts (2-3 A) of the atom positions and an only slight variation [I-2 kcal/mol) of energy. Even small shifts in other directions can cause a drastic energy increase. For some nucleotide sequences, the energetically preferable conformations are the B-like ones (e.g., ApA, TpA), whereas for others the A-like ones are preferable (e.g., GpG, ApT). In general, Pyr-Pur sequences have a tendency to a larger T and smaller H and D than Pur-Pyr sequences. A large body of experimental data on nucleic acid structure in fibers and in solutions can be explained by results obtained.

A model has been constructed for liquid water by means of the Monte Carlo method (Metropolis procedure). In the ensemble of instantaneous configurations at 300~ (I-structures), a geometric criterion of hydrogen bonds has made it possible to detect 18 types of coordination of molecules. Less than 0.02% of the molecules formno hydrogen bonds whatsoever, and about 45% are tetrahedrally coordinated. Approximately 1.5% of the molecules participate in forked (bifurcate) bonds. However, in the analysis of instantaneous configurations, it is impossible in p~inciple to propose any unambiguous criterion in searching for hydrogen bonds. One of the I-structures was "frozen"; i.e., the Metropolis procedure was used to find a local minimum in the space of potential energies that is closest to this structure.

The energies and structures of many small water clusters (H20)n (n = 8-26) are calculated using the atom-atom potential functions suggested earlier. For each n, several stable configurations were found that differ in the number of H-bonds and in the topology of the graphs formed by such bonds. The clusters in which the molecules lie at the vertices of convex polyhedra have the lowest-energy but other configurations may have close or even lower energies. For the most stable clusters, the energy dependence on n is close to linear. At 300 K, the mean energies of the clusters behave similarly. Monte-Carlo simulations showed that the clusters undergo pseudomelting at approximately 200 K.

xTo explain biochemical and genetic data on spontaneous nucleotide replacements in nucleic acid biosynthesis all the 8 mispairs in normal tautomferic forms have been considered. Possible B-conformations of DNA fragments containing each of such mispairs incorporated between Watson-Crick pairs have been found using computations of the energy of non-bonded interactions via classical potential functions. These conformations have no reduced interatomic contacts. The values of each dihedral angle of the sugar-phosphate backbone fall within the limits of those of double-helical fragments of B-DNA in crystals. These values differ from those of the corresponding angles for the low-energy polynucleotide conformations consisting of canonical pairs by no more than 300 (except for the fragment with the U:U pair for which the C -Cj-O-P angle differs by about 50"). The difference in experimentally observed frequencies of various nucleotide replacements in DNA biosynthesis correlates with the difference in the energy of non-bonded interactions and with the extent of the sugar-phosphate backbone distortion for the fragments containing the mispairs which serve as intermediates for the replacements.

A system of atom-atom potential functions for computer simulation of aqueous solutions of DNA fragments and eounterions was developed. Hydration of Na +, K +, and dimethyl phosphate (DMP-) ions was simulated by the Monte Carlo method. The obtained energy and structural characteristics of the solutions reproduce well the experimental data and are in good agreement with the results of ab initio calculations carried out by other authors.

Interactions with water molecules are important for the stabilization of three-dimensional structures of nucleic acids and for their functioning. The first hydration shells of macromolecules can be considered as structural parts of nucleic acid. We performed a Monte Carlo study of systems containing a nucleic acid base or base pair with water molecules using improved potential functions. These potential functions enable experimental data on both single base-single water interaction energies and enthalpies of base hydration to be reproduced. Hydration shell structures of base pairs are dependent on the pair geometry. Structural elements of hydration shells can contribute to the pair stability and hence to the probability of mispair formation during nucleic acid biosynthesis. The distribution of water molecules around bases and base pairs is essentially nonhomogeneous.

DFT studies of desoxydinucleoside monophosphate complexes with Na-ions (dDMPs), using DGAUSS and ADF software reveal that the characteristic B-type conformation of DNA duplexes is initially predisposed in single strand in the form of a local minimum. Such predisposition may be important for biological functioning of DNA by facilitating an addition of new nucleotide in the processes of DNA duplication and restoration of double helix after unwinding. The computational results demonstrate the important contribution of intra-strand interactions to conformational stability and sequence-dependent variability of B-DNA duplexes. The main characteristics of the ''canonical" BI conformations, such as the regions of torsion angles of sugar-phosphate backbone, C2 0 -endo or very close to C2 0 -endo sugar puckerings, and nearly parallel base-ring arrangements are already present in the single strand and are universal for all 16 dDMPs. The dihedral angle between the bases does not depend on the extent of their overlap, which suggests the major contribution of sugar-phosphate backbone to formation of these minima. The study reveals characteristic sequence dependence of the base arrangements. Namely, an extensive base-ring overlap takes place for all purine-purine and purine-pyrimidine sequences, and negligible ring overlap is observed in all pyrimidine-purine and pyrimidine-pyrimidine sequences. These arrangements closely resemble the geometrical characteristics of BI DNA in duplex crystals. Preliminary results of search for other energy minima related to helical DNA structures revealed the existence of BII-like minima for some dDMPs.

To approach atomic level mechanisms of caffeine biological activity, molecular mechanics computations of interactions between caffeine molecule and DNA duplex fragments, containing four nucleotide pairs, have been performed. The calculations reveal a set of energy minima referring to rather compact caffeine arrangement in both major and minor grooves of the helix. The set includes the minima correspondent to the H-bond formation by any of the three proton acceptor atoms of caffeine with any of the three amino groups of DNA bases. Both H-bonded to caffeine nucleotides and some neighbor nucleotides of both chains contribute substantially to the total interaction energy. A possibility of caffeine complexation with DNA duplex suggests a possible mechanism of caffeine influence on DNA functioning via its competition with other ligands. q