Sequence-dependent B<-->A transition in DNA evaluated with dimeric and trimeric scales.

Experimental data on the sequence-dependent B<-->A conformational transition in 24 oligo- and polymeric duplexes yield optimal dimeric and trimeric scales for this transition. The 10 sequence dimers and the 32 trimers of the DNA duplex were characterized by the free energy differences between the B and A forms in water solution. In general, the trimeric scale describes the sequence-dependent DNA conformational propensities more accurately than the dimeric scale, which is likely related to the trimeric model accounting for the two interfaces between adjacent base pairs on both sides (rather than only one interface in the dimeric model). The exceptional preference of the B form for the AA:TT dimers and AAN:N'TT trimers is consistent with the cooperative interactions in both grooves. In the minor groove, this is the hydration spine that stabilizes adenine runs in B form. In the major groove, these are hydrophobic interactions between the thymine methyls and the sugar methylene groups from the preceding nucleotides, occurring in B form. This interpretation is in accord with the key role played by hydration in the B<-->A transition in DNA. Importantly, our trimeric scale is consistent with the relative occurrences of the DNA trimers in A form in protein-DNA cocrystals. Thus, we suggest that the B/A scales developed here can be used for analyzing genome sequences in search for A-philic motifs, putatively operative in the protein-DNA recognition.

Monte Carlo simulation of DNA fragment hydration in the presence of alkaline cations using novel atom-atom potential functions.

The set of atom-atom potential functions specially adjusted to simulation of nucleic acid fragment hydration (Poltev, Grokhlina & Malenkov, J. Biomol. Struct. Dyn. 2, 413, 1984) is extended by including alkaline cation interactions. The choice of new potential functions was realized using experimental data on crystal hydrates of nucleotides and related compounds as well as thermodynamic data on ion solutions. The extended set of potential functions allows to reproduce many features of interactions between alkaline cations and nucleic acid fragments in water solutions. The sites of preferential cation localization near bases and phosphate groups were obtained and examined. The potential functions reproduce the dissociation tendency of cation-phosphate group and cation-base complexes in aqueous medium. Pathways of cation dissociations from nucleic acid components have been studied, and metastable water-bridged positions of cations near bases and phosphate group have been revealed.

Modeling DNA hydration: comparison of calculated and experimental hydration properties of nuclic acid bases.

Hydration properties of individual nucleic acid bases were calculated and compared with the available experimental data. Three sets of classical potential functions (PF) used in simulations of nucleic acid hydration were juxtaposed: (i) the PF developed by Poltev and Malenkov (PM), (ii) the PF of Weiner and Kollman (WK), which together with Jorgensen's TIP3P water model are widely used in the AMBER program, and (iii) OPLS (optimized potentials for liquid simulations) developed by Jorgensen (J). The global minima of interaction energy of single water molecules with all the natural nucleic acid bases correspond to the formation of two water-base hydrogen bonds (water bridging of two hydrophilic atoms of the base). The energy values of these minima calculated via PM potentials are in somewhat better conformity with mass-spectrometric data than the values calculated via WK PF. OPLS gave much weaker water-base interactions for all compounds considered, thus these PF were not used in further computations. Monte Carlo simulations of the hydration of 9-methyladenine, 1-methyluracil and 1-methylthymine were performed in systems with 400 water molecules and periodic boundary conditions. Results of simulations with PM potentials give better agreement with experimental data on hydration energies than WK PF. Computations with PM PF of the hydration energy of keto and enol tautomers of 9-methylguanine can account for the shift in the tautomeric equilibrium of guanine in aqueous media to a dominance of the keto form in spite of nearly equal intrinsic stability of keto and enol tautomers. The results of guanine hydration computations are discussed in relation to mechanisms of base mispairing errors in nucleic acid biosynthesis. The data presented in this paper along with previous results on simulation of hydration shell structures in DNA duplex grooves provide ample evidence for the advantages of PM PF in studies of nucleic-acid hydration.

[The mechanism of tautomeric transitions of nucleic acid bases with limited access to water molecules]. / O mekhanizme tautomernykh prevrashchenii osnovanii nukleinovykh kislot v usloviiakh ogranichennogo dostupa k nim molekul vody.

Pathways of tautomeric transformations of nucleic acid bases have been considered in the conditions when only few separate water molecules can interact with the bases. Field ionization mass-spectrometric study has demonstrated that substitution of one of the labile hydrogen atoms for deuterium takes place when thymine (or 1-methylthymine) interacts with heavy water in vacuo. This observation was explained by a supposition that a transient water-thymine complex is formed and then tautomeric transition of the base occurs via double proton transfer along hydrogen bonds. Calculations of the interaction energy between base and water molecules allowed us to suggest the structure of such a complex in which water molecule lays in the plane of the base. Formation of such complexes during biosynthesis of nucleic acids can give rise to point errors, probability of their appearance being dependent on the structure and properties of a macromolecular DNA-enzyme-nucleotide complex.

[Monte-Carlo simulation of hydration of nucleic acid fragments]. / Modelirovanie gidratatsii fragmentov nukleinovykh kislot metodom Monte-Karlo.

Monte-Carlo simulation of the systems containing a stack of 6 complementary base pairs and 180 water molecules has been performed. Characteristic of the hydration shell structure in major and minor grooves has been found for the stacks of repeating A : U and G : C base pairs as well as alternating (A : U, U : A) and (G : C, C : G) ones. Probabilities of the formation of bridges, formed by 1, 2 and 3 water molecules, between hydrophilic centres of the bases have been estimated. One water molecule forms an H-bonded bridge between two adjacent hydrophilic centres with high probability if N...N, N...O or O...O distance between these centres is close to 4.3 A. Hydration shell structure was found to depend significantly on the stack sequence and configuration, while global hydration characteristics (average energy, the number of water-water and water-base H-bonds) are only slightly dependent on the stack sequence and configuration. For the stacks in A conformation the number of water molecules forming more than one H-bonds with the bases is greater in comparison with the stacks in B-like conformation. This result is discussed in connection with the concept of hydration economy during B to A transition.

Monte Carlo simulation of hydration of the nucleic acid fragments.

Systems containing a base or a base pair and 25 water molecules, as well as a helical stack and 30 water molecules per base pair, have been simulated. Changes in the base hydration shell structure, after the bases have been included into the pair and then into the base pair stack, are discussed. Hydration shells of several configurations of the base pair stacks are discussed. Probabilities of formation of the hydrogen-bonded bridges of 1, 2 and 3 water molecules between hydrophilic centres have been estimated. The hydration shell structure was shown to depend on the nature of the base pair and on the stack configuration, while dependence of the global hydration shell characteristics on the stack configuration has been proved to be rather slight. The most typical structural elements of hydration shells, in the glycosidic (minor in B-like conformation) and non-glycosidic (major) grooves, for different configurations of AU and GC stacks, have been found and discussed. The number of hydrogen bonds between water molecules and bases per water molecule was shown to change upon transformation of the stack from A to B configuration. This result is discussed in connection with the reasons for B to A conformational transition and the concept of "water economy". Hydration shell patterns of NH2-groups of AU and GC helical stacks differ significantly.

[Study of the hydration characteristics of nucleic acid bases and their complementary pairs using the Monte-Carlo method]. / Izuchenie osobennostei gidratatsii osnovanii nukleinovykh kislot i ikh komplementarnykh par metodom Monte-Karlo.

To elucidate the role of certain atomic groups in the formation of the nucleic acid hydrate shell, we simulated the systems involving a base or a complementary pair (the base molecules are methylated in N9 of purines and in N1 of pyrimidines) and 25 water molecules using the Monte-Carlo method. All hydrophilic centers, except for N1 purines and N3 pyrimidines in complementary pairs, form hydrogen bonds (H-bonds) with water molecules. The mean numbers of H-bonds formed by different centers, and distributions of the geometric characteristics of these bonds, which appeared similar to those in crystals, have been calculated. The formation of bridges of one, two of three water molecules between hydrophilic centers was shown. The probabilities of formation of these bridges have been calculated.

[Determination of enthalpy of B-A transition of DNA in aqueous-ethanol solutions]. / Opredelenie éntal'pii konformatsionnogo B-A perekhoda DNK v vodno-étanol'nykh rastvorakh.

The enthalpies of the guanidinium chloride (Gu.HCl) with sodium DNA salt in the solutions in B- and A-conformations in the mixtures of ethanol-water at 298.15 K and the enthalpies of solution of guanidinium chloride in the mixtures of ethanol-water at 298.15 K in a whole range of the compositions of mixed solvents were measured calorimetrically. It was established that in a field of B-A-transition of DNA the values of interaction enthalpies of Gu.HCl with DNA practically do not depend on the composition of the solvent. The concentrations of Na-ions in water-ethanol solutions of DNA containing Gu.HCl were determined by the potentiometric method. It was revealed that the interaction of the equimolar quantities of Gu.HCl and DNA leads to the complete replacement of Na-cations, which are naturally linked with DNA, into solution. From the results obtained the enthalpy of B-A-conformation transition DNA at 298.15 K was determined (-2.50 +/- 0.10 kJ/mole).

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.

[Computer simulation of protein molecular dynamics]. / Chislennoe modelirovanie molekuliarnoi dinamiki belkov.

A review of the works on the computer simulation of the globular protein dynamics is given. Methodological aspects of the simulation procedure are outlined briefly. Main peculiarities of protein dynamics revealed in the course of simulation of pancreatic trypsin inhibitor and cytochrome c are presented. The causes of "anomalous" processes, inherent in the simulated behaviour of model proteins are discussed. These "anomalous" processes are: continuous drift of the structure and its deviation from the experimental one, determined by X-ray analysis. Both processes are supposed to be the consequence of the reduced conformational rigidity of the model protein in comparison to the real one. Among the possible reasons for this reduced rigidity absence of the water molecules, hydrating peptide groups in the real protein, may be mentioned. Analogy between "anomalous" processes in the simulated protein dynamics and some phenomena observed in the real proteins during their functioning is drawn.

[Survival of the mutant clone. III. Catastrophic selection. The inadequacy of the selection coefficient for assessing clone fate]. / Vyzhivanie mutantnogo klona. Soobshchenie III. Katastroficheskii otbor. Nedostatochnost' koéffitsienta otbora dlia otsenki sud'by klona.

Majorant estimations of the probabilities pr for the surviving of the clone of the dividing cells have been obtained in the catastrophic situation (monotonous diminishing of the clone almost to zero during the period of time from t=0 to t=T, T approximately 100 generation). At t=0 the clone consisted of 10(6) individuals. Average selection coefficient (s) was found to determine pr only roughly, that is the clone with s greater than --0.09 survives almost in all cases, whereas the clone with s greater than --0.13 becomes extinct practically always. Within this interval ps-inversion can be observed, i.e. preferential surviving of the clone with a worse s value. Results of three communications lead to the conclusion that the mutants with small selective advantage practically cannot be selected.

[Polarity of the environment as a factor determining DNA conformation]. / Poliarnost' okruzheniia kak faktor, opredeliaiushchii konformatsiiu DNK.

Polarity of double and ternary water-nonelectrolyte systems at the component ratio, corresponding to a half-transition point of DNA from B to A form was evaluated from ESR spectra of a spin-probe. In all cases examined the isotropic super-fine splitting constant (aN) is the same with an accuracy of 0.05 gauss. Small differences in aN are well correlated with the concentration of the groups which are able to form hydrogen bonds with the nitroxide fragment of the radical. Thus, media polarity is a factor which determines the A--B equilibrium of DNA in solution.

[B-A transition of DNA in aqueous solutions of nonelectrolytes]. / B-A-perekhod DNK v vodnykh rastvorakh neélektrolitov.

Circular dichroism spectra of DNA in ternary water-nonelectrolyte solutions (water--ethanol--isopropanol and water--ethanol--dioxane) show that the decrease in water content at various nonelectrolyte ratios leads to the transition of DNA from B- to A-form. Water activity values in B-A transition region were calculated. The transition takes place within the range of water activity and DNA conformations have been plotted on triangular diagrams.

[Estimation of the enthalpy of B--A transitions in DNA in water-ethanol solutions]. / Otsenka éntal'pii B--A-perekhoda DNK v vodno-étanol'nykh rastvorakh

Enthalpy of reaction of guanidinium chloride with sodium DNA salt was determined microcalorimetrically at 25 degrees C in water-ethanol solutions of various concentrations. At low ethanol contents (up to 25 mole%) reaction is exothermic, its enthalpy being only slightly dependent on ethanol concentration. Above 28 41 mole % of ethanol reaction becomes endothermic. As above 41 mole% of ethanol in the absence of guanidinium ions A-type DNA conformation appears in the solution, which under the influence of guanidinium is converted to the B-type conformation, enthalpy of conformation transition must be included in the measured enthalpy of the reaction. Dependence of the measured enthalpy on ethanol concentration in the B--A transition region testifies to a very small value of the enthalpy change during this transition.

[A study of the physico-chemical properties of lecithin membranes using hydrophobic and hydrophilic spin probes]. / Issledovanie fiziko-khimicheskikh svoistv letsitinovykh membran pri pomoshchi gidrofobnykh i gidrofil'nykh spinovykh zondov

Some physico-chemical properties of lecithin lyposomes and the effects of pH, temperature and ionic strength changes are studied by ESR using hydrophobic and hydrophylic nitroxyl radicals as spin probes. The structure differences between outer and inner layers of bilayer liposomes are observed using auxiliary water soluble paramagnetic complex and attributed tentatively to the different curvature signs of both layers. Lower estimates of transversal diffusion rates of both probes throught the membrane are obtained using exchange broadening technique and water soluble reducing agent. The limiting step in this diffusion is revealed, caused by the transport of a charged group of the diffusing molecule through the hydrophobic membrane space.

[A stereochemical model for DNA-Na+ (H20) complex]. / Prostranstvennaia model' kompleksa DNK-gidrat Na+

By computer calculation with the use of atom-atom potentials a stereochemical model of the DNA-hydrate Na+ complex was obtained according to which the Na+(H2O)6 octahedrons are localized in the narrow groove of DNA with formation of a great number of van der vaals contacts and hydrogen bonds. The model explains why the C-form of DNA is stabilized in the Na-DNA complex which is formed in the presence of 80% methanol (v/v). A possibility of the existence of such complexes in vivo at the DNA regions surrounded with media of diminished water activity (the DNA-membrane complex, chromosomes, phage heads) is discussed.