A Theoretical Study of the Aqueous Hydration of Canonical B d(CGCGAATTCGCG): Monte Carlo Simulation and Comparison with Crystallographic Ordered Water Sites

Abstract

Monte Carlo computer simulation is described for the dodecamer d(CGCGAATTCGCG) together with 1777 water molecules at an environmental density of 1 gm/cc in a cubic cell under periodic boundary conditions. Water-water interactions were treated using the TIP4P potential and the solute water interactions by TIP4P spliced with the non-bonded interactions from the AMBER 3.0 force field. The simulation was subjected to proximity analysis to obtain solute coordination numbers and pair interaction energies for each solute atom. Hydration density distributions partitioned into contributions from the major groove side, the minor groove side and the sugar-phosphate backbone were examined, and the probabilities of occurence for one- and two-water bridges in the simulation were enumerated. The results were compared with observations of crystallographic ordered water sites from x-ray diffraction studies on the native dodecamer by Dickerson and coworkers.     

A Monte Carlo simulation study of the aqueous hydration of r(GpC)2: comparison with crystallographic ordered water sites

Monte Carlo computer simulation is described for the dinucleotide duplex rGpC together with 562 water molecules at an environmental density of 1 g/cc in a cubic cell under periodic boundary conditions. Water-water interactions were treated using the TIP4P potential and the solute water interactions by TIP4P spliced with the nonbonded interactions from the AMBER 3.0 force field. The simulation was subjected to proximity analysis to obtain solute coordinate numbers and pair interaction energies for each solute atom. Hydration density distributions partitioned into contributions from the major groove side, the minor groove side and the sugar-phosphate backbone were examined, and the probabilities of occurrence for one- and two-water bridges in the simulation were enumerated. The results were compared with observations of crystallographic ordered water sites from x-ray diffraction studies on G and C containing small molecules, and in crystal structure determinations of the sodium, calcium, and ammonium salts of rGpC. The calculated results are generally consistent with the observed sites, except for cytosine N4, where a hydration site is predicted yet none observed in rGpC salts, and for guanine N3, which appears in this calculation to compete unfavorably with the adjacent donor site at guanine N2. There is, however, a significant probability of finding a one-water G-N3-W-G-N2 bridge indicated in the simulation. An explanation for the guanine N3 discrepancy in terms of electrostatic potentials is also offered. The calculated one- and two-water bridges in the rGpC hydration complex coincide in a number of cases to those observed in the ordered water structure of the sodium rGpC crystal hydrate.     

Molecular dynamics study of substance P peptides in a biphasic membrane mimic

Two neuropeptides, substance P (SP) and SP-tyrosine-8 (SP-Y8), have been studied by molecular dynamics (MD) simulation in a TIP3P water/CCl4 biphasic solvent system as a mimic for the water-membrane system. Initially, distance restraints derived from NMR nuclear Overhauser enhancements (NOE) were incorporated in the restrained MD (RMD) in the equilibration stage of the simulation. The starting orientation/position of the peptides for the MD simulation was either parallel to the water/CCl4 interface or in a perpendicular/insertion mode. In both cases the peptides equilibrated and adopted a near-parallel orientation within approximately 250 ps. After equilibration, the conformation and orientation of the peptides, the solvation of both the backbone and the side chain of the residues, hydrogen bonding, and the dynamics of the peptides were analyzed from trajectories obtained in the RMD or the subsequent free MD (where the NOE restraints were removed). These analyses showed that the peptide backbone of nearly all residues are either solvated by water or are hydrogen-bonded. This is seen to be an important factor against the insertion mode of interaction. Most of the interactions with the hydrophobic phase come from the hydrophobic interactions of the side chains of Pro-4, Phe-7, Phe-8, Leu-10, and Met-11 for SP, and Phe-7, Leu-10, Met-11 and, to a lesser extent, Tyr-8 in SP-Y8. Concerted conformational transitions took place in the time frame of hundreds of picoseconds. The concertedness of the transition was due to the tendency of the peptide to maintain the necessary secondary structure to position the peptide properly with respect to the water/CCl4 interface.     

Energetics of water proton configurations in gas hydrates: comparison of various water models

The total interaction energies for a large number of water proton configurations in the unit cell of hydrate structure I consisting of 46 molecules are compared for qualitatively different water models, such as SPC/E, TIP4P, TIP5P, TIP 3f and AMOEBA. All calculations were carried out using the TINKER molecular modelling package. The Ewald summation method with metallic tin-foil boundary conditions is used to account for long-range electrostatic interactions. It was established that there is a high correlation between the energies calculated using the five water models (interaction potentials). The average correlation coefficient for all pairs of potentials is equal to 0.91. Analogous calculations were carried out to evaluate the consistency of the different water models with respect to a new property of the ice-like system: the hydrogen-bond-reversal asymmetry. It was established that, for all water models, there is relatively high correlation between the energy differences for proton configurations with opposite direction of all hydrogen bonds. In this case, the average correlation coefficient is 0.77. Data for the TIP4P potential differ noticeably from the others, especially owing to the variation in the total interaction energy. The validity and usefulness of simple discrete models of inter-molecular interactions are discussed.     

A Robust Water Potential Parameterisation

Abstract

We compare molecular dynamics simulation results for the properties of liquid water predicted by four novel water potential models. These models are designed as a combination of parameters taken from the dedicated but brittle TIP3P water potential, and the more flexible but less accurate parameterisations such as the Dreiding and Universal force fields. We find that a hybrid of Dreiding and TIP3P delivers the best results, yielding a density, diffusion coefficient and radial distribution function in good agreement with experiment, performing in some respects even better than the dedicated reference TIP3P model. Another Dreiding based force field predicts semi-quantitative results for the water structure and dynamics while the Universal force field based models are incapable of simulating a condensed phase of water at all, continuing to expand indefinitely. These observations are useful for selecting and designing robust water force field parameterisations that can be used for general simulation purposes.     

Structural insights into the effect of hydration and ions on A-tract DNA: a molecular dynamics study

DNA structure is known to be sensitive to hydration and ionic environment. To explore the dynamics, hydration, and ion binding features of A-tract sequences, a 7-ns Molecular dynamics (MD) study has been performed on the dodecamer d(CGCAAATTTGCG)(2). The results suggest that the intrusion of Na(+) ion into the minor groove is a rare event and the structure of this dodecamer is not very sensitive to the location of the sodium ions. The prolonged MD simulation successfully leads to the formation of sequence dependent hydration patterns in the minor groove, often called spine of hydration near the A-rich region and ribbon of hydration near the GC regions. Such sequence dependent differences in the hydration patterns have been seen earlier in the high resolution crystal structure of the Drew-Dickerson sequence, but not reported for the medium resolution structures (2.0 approximately 3.0 A). Several water molecules are also seen in the major groove of the MD simulated structure, though they are not highly ordered over the extended MD. The characteristic narrowing of the minor groove in the A-tract region is seen to precede the formation of the spine of hydration. Finally, the occurrence of cross-strand C2-H2.O2 hydrogen bonds in the minor groove of A-tract sequences is confirmed. These are found to occur even before the narrowing of the minor groove, indicating that such interactions are an intrinsic feature of A-tract sequences.     

Molecular structure of the netropsin-d(CGCGATATCGCG) complex: DNA conformation in an alternating AT segment

The molecular structure of the complex between a minor groove binding drug (netropsin) and the DNA dodecamer d(CGCGATATCGCG) has been solved and refined by single-crystal X-ray diffraction analysis to a final R factor of 20.0% to 2.4-A resolution. The crystal is similar to that of the other related dodecamers with unit cell dimensions of a = 25.48 A, b = 41.26 A, and c = 66.88 A in the space group P2(1)2(1)2(1). In the complex, netropsin binds to the central ATAT tetranucleotide segment in the narrow minor groove of the dodecamer B-DNA double helix as expected. However, in the structural refinement the drug is found to fit the electron density in two orientations equally well, suggesting the disordered model. This agrees with the results from solution studies (chemical footprinting and NMR) of the interactions between minor groove binding drugs (e.g., netropsin and distamycin A) and DNA. The stabilizing forces between drug and DNA are provided by a combination of ionic, van der Waals, and hydrogen-bonding interactions. No bifurcated hydrogen bond is found between netropsin and DNA in this complex due to the unique dispositions of the hydrogen-bond acceptors (N3 of adenine and O2 of thymine) on the floor of the DNA minor groove. Two of the four AT base pairs in the ATAT stretch have low propeller twist angles, even though the DNA has a narrow minor groove. Alternating helical twist angles are observed in the ATAT stretch with lower twist in the ApT steps than in the TpA step.     

Monte Carlo Study of Structural and Thermodynamic Properties of Liquid Chloroform Using a Five Site Model

A five site potential model combining Lennard–Jones plus Coulomb potential functions has been developed for chloroform molecule. The partial charges needed for Coulombic interactions were derived using the chelpg procedure implemented in the gaussian 92 program. These calculations were performed at the MP2 level with MC-311G* basis set for Cl and 6-311G** for C and H atoms. The parameters for the Lennard–Jones potentials were optimized to reproduce experimental values for the density and enthalpy of vaporization of the pure liquid at 298 K and 1 atm. The statistical mechanics calculations were performed with the Monte Carlo method in the isothermic and isobaric (NpT) ensemble. Besides the values obtained for density, ρ, and molar enthalpy of vaporization at constant pressure, Δ H_V, for liquid chloroform, results for molar volume, V_m, molar heat capacity, C_p, isobaric thermal expansivity, α_p, and isothermal compressibility, κ_T, for this pure liquid are also in very good agreement with experimental observations. Size effects on the values of thermodynamic properties were investigated. The potential model was also tested by computing the free energy for solvating one chloroform molecule into its own liquid at 298 K using a statistical perturbation approach. The result obtained compares well with the experimental value. Site–site pair correlation functions were calculated and are in good accordance with theoretical results available in the literature. Dipole–dipole correlation functions for the present five site model were also calculated at different carbon–carbon distances. These correlations were compared to those obtained using the four site model reported in the literature. An investigation of the solvent dependence of the relative free energy for cis/trans conversion of a hypothetical solute in TIP4P water and chloroform was accomplished. The results show strong interaction of water and chloroform molecules with the gauche conformer. The value obtained for the free energy barrier for cis/trans rotation in TIP4P water is higher than that for chloroform. This result is in agreement with the continuous theory for solvation as the conformer with higher dipole moment is more favoured by the solvent with higher dieletric constant. The results also show an increase in entropy as the solute goes from the cis to the trans geometry and this result is more appreciable in the aqueous solution. This revised version was published online in June 2006 with corrections to the Cover Date.     

Interactions between a symmetrical minor groove binding compound and DNA oligonucleotides: 1H and 19F NMR studies

High-resolution NMR techniques (proton and 19F) have been used to study the interactions between several DNA oligonucleotides with varying length of AT base pairs and the synthetic pyrrole-containing compound (P1-F4S-P1), which has properties similar to the DNA minor groove binding drug distamycin A. When this two-fold symmetrical DNA binding molecule is added to the self-complementary DNA oligomers, the resulting complex exhibits an NMR spectrum without any doubling of individual resonances, consistent with a two-fold symmetry of the complex. This is in contrast to all other complexes studied so far. The minimum length of an AT stretch for specific ligand binding is judged to be greater than 4 base pairs. Inter-molecular proton nuclear Overhauser effects between the ligand molecule and a DNA dodecamer d(CGCAAATTTGCG) provide evidence that P1-F4S-P1 binds DNA in the minor groove and interacts with the middle AT base pairs. The presence of a specific interaction between P1-F4S-P1 and DNA is conclusively demonstrated by 19F NMR studies, in which four previously chemically equivalent fluorine nuclei in the free molecule become two non-equivalent pairs (yielding an AB quartet pattern) upon the binding of P1-F4S-P1 to DNA duplex. A sequence-dependent binding behavior of P1-F4S-P1 is evident by comparing the 19F NMR spectra of the complexes between P1-F4S-P1 and two different but related DNA dodecamers, d(CGCAAATTTGCG) and d(CGCTTTAAAGCG). P1-F4S-P1 binds more strongly to the former dodecamer with an association constant of approximately 1 X 10(3) M-1.     

The Application of the Reaction-Field Method to the Calculation of Dielectric Constants

Abstract

The behaviour of the popular TIP3P water model has been investigated using both molecular dynamics and Monte Carlo simulation procedures. Long-range electrostatic interactions were included through a reaction-field treatment, and the nonbonded interactions were either truncated at the cutoff distance, or smoothly scaled to zero using a switching function. The thermodynamic observables, and in particular the dipole-dipole correlation functions, are found to differ between the two simulation techniques if a rigid nonbonded cutoff is applied. However, use of a switching function gives exact agreement between the simulation methodologies. This difference is ascribed to the effect of energy pumping in the molecular dynamics simulations, and suggests that dielectric constants calculated using this simulation method with the fluctuation procedure in conjunction with a reaction field should be reappraised. Thus the Monte Carlo simulation procedure offers a number of intrinsic advantages over molecular dynamics for the calculation of dielectric constants with a reaction field. The most precise value for the dielectric constant of TIP3P is calculated to be 102 ± 3 at 298 K.     

Structural comparison of the B-DNA dodecamers d(CGCGTTAACGCG) and d(CGCGAATTCGCG) with T2A2 and A2T2 tracts.

The x-ray structure of the deoxy oligonucleotide dodecamer d(CGCGTTAACGCG) recently determined in our laboratory shows that the helical parameters of the central TTAA segment are significantly different compared to the central AATT in d(CGCGAATTCGCG). The roll in the central TA step of the T2A2 dodecamer opens towards the minor groove while the AT step of the A2T2 dodecamer opens towards the major groove. Also, the roll angles at the steps 4 and 8 (GT and AC in T2A2) and (GA and TC in A2T2) are in opposite directions. The high cup and helical twist angles at the central base-pair of T2A2 decreases the base stacking interactions compared to A2T2. Tilt angles within the tetranucleotide segments TTAA and AATT have opposite signs. In spite of the local differences caused by the sequence inversion (TTAA----AATT), the two dodecamers exhibit similar overall bending. The top third is more bent than the bottom third relative to the central segment. This asymmetric bending in the two dodecamers is mainly due to crystal packing interactions.     

Structure and hydration of BamHI DNA recognition site: a molecular dynamics investigation

The results of a 3-ns molecular dynamics simulation of the dodecamer duplex d(TATGGATCCATA)(2) recognized by the BamHI endonuclease are presented here. The DNA has been simulated as a flexible molecule using an AMBER force field and the Ewald summation method, which eliminates the undesired effects of truncation and permits evaluation of the full effects of electrostatic forces. The starting B conformation evolves toward a configuration quite close to that observed through x-ray diffraction in its complex with BamHI. This configuration is fairly stable and the Watson-Crick hydrogen bonds are well maintained over the simulation trajectory. Hydration analysis indicates a preferential hydration for the phosphate rather than for the ester oxygens. Hydration shells in both the major and minor groove were observed. In both grooves the C-G pairs were found to be more hydrated than A-T pairs. The "spine of hydration" in the minor groove was clear. Water residence times are longer in the minor groove than in the major groove, although relatively short in both cases. No special long values are observed for sites where water molecules were observed by x-ray diffraction, indicating that water molecules having a high probability of being located in a specific site are also fast-exchanging.     

Hydration at the TD Damaged Site of DNA and its Role in the Formation of Complex with T4 Endonuclease V

Abstract

An analysis of the distribution of water around DNA surface focusing on the role of the distribution of water molecules in the proper recognition of damaged site by repair enzyme T4 Endonuclease V was performed. The native DNA dodecamer, dodecamer with the thymine dimer (TD) and complex of DNA and part of repair enzyme T4 Endonuclease V were examined throughout the 500 ps of molecular dynamics simulation. During simulation the number of water molecules close to the DNA atoms and the residence time were calculated. There is an increase in number of water molecules lying in the close vicinity to TD if compared with those lying close to two native thymines (TT). Densely populated area with water molecules around TD is one of the factors detected by enzyme during scanning process. The residence time was found higher for molecule of the complex and the six water molecules were found occupying the stabile positions between the TD and catalytic center close to atoms P, C3′ and N3. These molecules originate water mediated hydrogen bond network that contribute to the stability of complex required for the onset of repair process.     

Mediation of the A/B-DNA helix transition by G-tracts in the crystal structure of duplex CATGGGCCCATG

The crystal structure of the DNA dodecamer duplex CATGGGCCCATG lies on a structural continuum along the transition between A- and B-DNA. The dodecamer possesses the normal vector plot and inclination values typical of B-DNA, but has the crystal packing, helical twist, groove width, sugar pucker, slide and x-displacement values typical of A-DNA. The structure shows highly ordered water structures, such as a double spine of water molecules against each side of the major groove, stabilizing the GC base pairs in an A-like conformation. The different hydration of GC and AT base pairs provides a physical basis for solvent-dependent facilitation of the A↔B helix transition by GC base pairs. Crystal structures of CATGGGCCCATG and other A/B-DNA intermediates support a ‘slide first, roll later’ mechanism for the B→A helix transition. In the distribution of helical parameters in protein–DNA crystal structures, GpG base steps show A-like properties, reflecting their innate predisposition for the A conformation.     

Incorporation of cationic chains in the Dickerson-Drew dodecamer: correlation of energetics, structure, and ion and water binding

We have investigated the unfolding thermodynamics for incorporating cationic side chains in the Dickerson-Drew dodecamer duplex. Incorporation of two 3-aminopropyl-2'-deoxyuridine residues (one on each self-complementary strand) lowers the stability of the duplex. This reduction is driven by unfavorable heat contributions due to the removal of electrostricted water and higher exposure of polar and nonpolar atomic groups that immobilize structural water. These cationic chains effectively remove counterions from the major groove, neutralizing some negatively charged phosphates. The overall results are consistent with the NMR solution of the modified duplex that showed a small bend at each modified site.     

Temperature and ion concentration effects on the viscosity of Price–Brooks' TIP3P-PME water model

The viscosity of the Price–Brooks modified TIP3P water model is investigated for different temperatures and NaCl concentrations using molecular dynamics with long-range electrostatic interactions. The viscosity has been determined from the equilibrium fluctuations of the pressure tensor by the Green–Kubo formalism. At 298 K in salt-free conditions, the resulting viscosity is higher than the value reported by other authors for TIP3P water. The viscosity is shown to decrease with temperature and increase with salt concentration, such as in real water, but with an absolute value always about half of the experimental value in analogous conditions. This difference must be attributed to the simplicity and the empirical nature of the TIP3P model, and also to the properties chosen for the original parameterisation, which did not include viscosity. At the considered levels of salinity, the effect of temperature is predominant.     

Studies of base pair sequence effects on DNA solvation based on all-atom molecular dynamics simulations

Detailed analyses of the sequence-dependent solvation and ion atmosphere of DNA are presented based on molecular dynamics (MD) simulations on all the 136 unique tetranucleotide steps obtained by the ABC consortium using the AMBER suite of programs. Significant sequence effects on solvation and ion localization were observed in these simulations. The results were compared to essentially all known experimental data on the subject. Proximity analysis was employed to highlight the sequence dependent differences in solvation and ion localization properties in the grooves of DNA. Comparison of the MD-calculated DNA structure with canonical A- and B-forms supports the idea that the G/C-rich sequences are closer to canonical A- than B-form structures, while the reverse is true for the poly A sequences, with the exception of the alternating ATAT sequence. Analysis of hydration density maps reveals that the flexibility of solute molecule has a significant effect on the nature of observed hydration. Energetic analysis of solute-solvent interactions based on proximity analysis of solvent reveals that the GC or CG base pairs interact more strongly with water molecules in the minor groove of DNA that the AT or TA base pairs, while the interactions of the AT or TA pairs in the major groove are stronger than those of the GC or CG pairs. Computation of solvent-accessible surface area of the nucleotide units in the simulated trajectories reveals that the similarity with results derived from analysis of a database of crystallographic structures is excellent. The MD trajectories tend to follow Manning's counterion condensation theory, presenting a region of condensed counterions within a radius of about 17 A from the DNA surface independent of sequence. The GC and CG pairs tend to associate with cations in the major groove of the DNA structure to a greater extent than the AT and TA pairs. Cation association is more frequent in the minor groove of AT than the GC pairs. In general, the observed water and ion atmosphere around the DNA sequences is the MD simulation is in good agreement with experimental observations.