Dynamics Simulations Of Aqueous Solutions Research Articles

Orientational dynamics of water trapped between two nanoscopic hydrophobic solutes: A molecular dynamics simulation study

We investigate thoroughly the effect of confinement and solute topology on the orientational dynamics of water molecule in the interplate region between two nanoscopic hydrophobic paraffinlike plates. Results are obtained from molecular dynamics simulations of aqueous solutions of paraffinlike plates in the isothermal-isobaric ensemble. An analysis of survival time auto correlation function shows that the residence time of the water molecule in the confined region between two model nanoscopic hydrophobic plates depends on solute surface topology (intermolecular distance within the paraffinlike plate). As expected, the extent of confinement also changes the residence time of water molecules considerably. Orientational dynamics was analyzed along three different directions, viz., dipole moment, HH, and perpendicular to molecular plane vectors. It has been demonstrated that the rotational dynamics of the confined water does not follow the Debye rotational diffusion model, and surface topology of the solute plate and the extent of confinement have considerable effect on the rotational dynamics of the confined water molecules.

Force field design and molecular dynamics simulations of factor-inhibiting HIF-1 and its complex with known inhibitors: Implications for rational inhibitor design

Based on molecular dynamics simulations in aqueous solution, we investigate the dynamic properties of factor-inhibiting HIF-1 (FIH1) and its complexes with the substrate 2-oxoglutarate (2OG) and the two known inhibitors, N-oxalylglycine (NOG) and N-oxalyl- d-phenylalanine (NODP). The results obtained with the newly developed force field parameters for the coordination environment of the active-site ferrous ion show that FIH1 undergoes a significant conformational stabilization with a decrease in motional amplitude upon binding of the substrate or the inhibitors. Two loop structures around the active-site reveal a high flexibility in the resting form of FIH1 with the high B-factor values. These high-amplitude motions of the flexible loops are found to be weakened significantly in the presence of the substrate or a weak inhibitor (NOG), and damped out upon binding of a potent and selective inhibitor (NODP) in the active site. A characteristic feature that discriminates the coordination structures of the active-site ferrous ion in complex with 2OG and NOG in solution from those in the X-ray crystal structures lies in the presence of a structural water molecule from bulk solvent at the sixth coordination position, which leads to the formation of a stable octahedral coordination geometry. However, the approach of such a structural water molecule to the active-site ferrous ion is prohibited in the FIH1–NODP complex, which should be attributed to the formation of hydrophobic contacts between the phenyl ring of the inhibitor and the side chains of Tyr102, Leu186, and Trp296 at the entrance of the active site. This indicates that the d-enantiomeric side-chain phenyl group of NODP should play an essential role in potent and selective inhibition of FIH1.

On the Compatibility Criteria for Protein Encapsulation inside Mesoporous Materials

The properties of the enzyme pepsin, relevant to its incorporation inside the channels of mesoporous silica materials in the preparation of bioinorganic hybrids, are highlighted by molecular dynamics simulations of aqueous solutions of the protein under conditions optimal for encapsulation in SBA-15. The protein size, shape, flexibility and surface properties are calculated with the aim of deriving general accessibility/compatibility criteria favouring encapsulation inside mesoporous systems.

Observation of Pyridine Aggregation in Aqueous Solution Using Neutron Scattering Experiments and MD Simulations

Neutron diffraction with isotopic substitution (NDIS) experiments have been used to examine the structuring of aqueous solutions of pyridine. A new method is described for extracting the structure factors relating to intermolecular correlations from neutron scattering experiments on liquid solutions of complex molecular species. This approach performs experiments at different concentrations and exploits the intramolecular coordination number concentration invariance (ICNCI) to separate the internal and intermolecular contributions to the total intensities. The ability of this method to deconvolute molecular and intermolecular correlations is tested and demonstrated using simulated neutron scattering results predicted from molecular dynamics simulations of aqueous solutions of the polyatomic solute pyridine in which the inter- and intramolecular terms are known. The method is then implemented using neutron scattering measurements on solutions of pyridine. The results confirm that pyridine shows a significant propensity to aggregate in solution and demonstrate the prospects for the future application of the ICNCI approach to the study of large polyatomic solutes using next-generation neutron sources and detectors.

Dynamics of water at the nanoscale hydrophobic confinement

We investigate the effect of solute surface topology created by considering various intermolecular separations of the hydrophobic, paraffinlike plates on the dynamics of water confined between two such plates. The solute plates are made up of 5 n-C(18)H(38) molecules arranged in parallel in such a way that all the carbon atoms of the paraffin molecule are lying on the same plane. Results are obtained from extensive molecular dynamics simulations of aqueous solutions of paraffinlike plates in the isothermal-isobaric ensemble. A strong dependence of the translational as well as vibrational dynamics of the confined water molecules on surface topology (intermolecular distance within the paraffinlike plate) has been observed. Analysis of mean squared displacement reveals anomalous nonlinear behavior of the water molecules in the nanoconfined environment.

Unraveling the molecular mechanisms of nitrogenase conformational protection against oxygen in diazotrophic bacteria

BackgroundG. diazotrophicus and A. vinelandii are aerobic nitrogen-fixing bacteria. Although oxygen is essential for the survival of these organisms, it irreversibly inhibits nitrogenase, the complex responsible for nitrogen fixation. Both microorganisms deal with this paradox through compensatory mechanisms. In A. vinelandii a conformational protection mechanism occurs through the interaction between the nitrogenase complex and the FeSII protein. Previous studies suggested the existence of a similar system in G. diazotrophicus, but the putative protein involved was not yet described. This study intends to identify the protein coding gene in the recently sequenced genome of G. diazotrophicus and also provide detailed structural information of nitrogenase conformational protection in both organisms.ResultsGenomic analysis of G. diazotrophicus sequences revealed a protein coding ORF (Gdia0615) enclosing a conserved “fer2” domain, typical of the ferredoxin family and found in A. vinelandii FeSII. Comparative models of both FeSII and Gdia0615 disclosed a conserved beta-grasp fold. Cysteine residues that coordinate the 2[Fe-S] cluster are in conserved positions towards the metallocluster. Analysis of solvent accessible residues and electrostatic surfaces unveiled an hydrophobic dimerization interface. Dimers assembled by molecular docking presented a stable behaviour and a proper accommodation of regions possibly involved in binding of FeSII to nitrogenase throughout molecular dynamics simulations in aqueous solution. Molecular modeling of the nitrogenase complex of G. diazotrophicus was performed and models were compared to the crystal structure of A. vinelandii nitrogenase. Docking experiments of FeSII and Gdia0615 with its corresponding nitrogenase complex pointed out in both systems a putative binding site presenting shape and charge complementarities at the Fe-protein/MoFe-protein complex interface.ConclusionsThe identification of the putative FeSII coding gene in G. diazotrophicus genome represents a large step towards the understanding of the conformational protection mechanism of nitrogenase against oxygen. In addition, this is the first study regarding the structural complementarities of FeSII-nitrogenase interactions in diazotrophic bacteria. The combination of bioinformatic tools for genome analysis, comparative protein modeling, docking calculations and molecular dynamics provided a powerful strategy for the elucidation of molecular mechanisms and structural features of FeSII-nitrogenase interaction.

Molecular dynamics simulations of aqueous solutions of ionic liquids

We performed a molecular dynamics study of aqueous solutions of ionic liquids 1-butyl-3-methylimidazolium chloride ([BMIM]Cl) and 1-octyl-3-methylimidazolium chloride ([OMIM]Cl) in order to elucidate the anomalous dependence of the surface tension on concentration. We found that cations are placed preferably at the surface with alkyl chains pointing towards vacuum. Anions compensate the surplus of a positive charge on the surface by forming a layer below the cation layer. At lower concentrations the surface tension decreases with concentration. At higher concentrations the surface becomes saturated by cations and the decrease slows down. The decrease of surface tension with concentration is a consequence of the structural changes, although the experimentally observed anomalous increase at even higher concentrations was not reproduced.

Ion Specificity at the Peptide Bond: Molecular Dynamics Simulations of N-Methylacetamide in Aqueous Salt Solutions

Affinities of alkali cations and halide anions for the peptide group were quantified using molecular dynamics simulations of aqueous solutions of N-methylacetamide using both nonpolarizable and polarizable force fields. Potassium and, more strongly, sodium exhibit an affinity for the carbonyl oxygen of the amide group, while none of the halide anions shows any appreciable attraction for the amide hydrogen. Heavier halides, however, interact with the hydrophobic methyl groups of N-methylacetamide. Using the present results for a model of the peptide bond we predict that the destabilizing effect of weakly hydrated Hofmeister ions, such as bromide or iodide, is not due to direct interactions with the backbone but rather due to attraction to hydrophobic regions of the protein.

Translational, rotational and internal dynamics of amyloid β-peptides (Aβ40 and Aβ42) from molecular dynamics simulations

In this study, diffusion constants [translational (D(T)) and rotational (D(R))], correlation times [rotational (tau(rot)) and internal (tau(int))], and the intramolecular order parameters (S(2)) of the Alzheimer amyloid-beta peptides Abeta40 and Abeta42 have been calculated from 150 ns molecular dynamics simulations in aqueous solution. The computed parameters have been compared with the experimentally measured values. The calculated D(T) of 1.61 x 10(-6) cm(2)/s and 1.43 x 10(-6) cm(2)/s for Abeta40 and Abeta42, respectively, at 300 K was found to follow the correct trend defined by the Debye-Stokes-Einstein relation that its value should decrease with the increase in the molecular weight. The estimated D(R) for Abeta40 and Abeta42 at 300 K are 0.085 and 0.071 ns(-1), respectively. The rotational (C(rot)(t)) and internal (C(int)(t)) correlation functions of Abeta40 and Abeta42 were observed to decay at nano- and picosecond time scales, respectively. The significantly different time decays of these functions validate the factorization of the total correlation function (C(tot)(t)) of Abeta peptides into C(rot)(t) and C(int)(t). At both short and long time scales, the Clore-Szabo model that was used as C(int)(t) provided the best behavior of C(tot)(t) for both Abeta40 and Abeta42. In addition, an effective rotational correlation time of Abeta40 is also computed at 18 degrees C and the computed value (2.30 ns) is in close agreement with the experimental value of 2.45 ns. The computed S(2) parameters for the central hydrophobic core, the loop region, and C-terminal domains of Abeta40 and Abeta42 are in accord with the previous studies.

An image-based reaction field method for electrostatic interactions in molecular dynamics simulations of aqueous solutions.

In this paper, a new solvation model is proposed for simulations of biomolecules in aqueous solutions that combines the strengths of explicit and implicit solvent representations. Solute molecules are placed in a spherical cavity filled with explicit water, thus providing microscopic detail where it is most needed. Solvent outside of the cavity is modeled as a dielectric continuum whose effect on the solute is treated through the reaction field corrections. With this explicit/implicit model, the electrostatic potential represents a solute molecule in an infinite bath of solvent, thus avoiding unphysical interactions between periodic images of the solute commonly used in the lattice-sum explicit solvent simulations. For improved computational efficiency, our model employs an accurate and efficient multiple-image charge method to compute reaction fields together with the fast multipole method for the direct Coulomb interactions. To minimize the surface effects, periodic boundary conditions are employed for nonelectrostatic interactions. The proposed model is applied to study liquid water. The effect of model parameters, which include the size of the cavity, the number of image charges used to compute reaction field, and the thickness of the buffer layer, is investigated in comparison with the particle-mesh Ewald simulations as a reference. An optimal set of parameters is obtained that allows for a faithful representation of many structural, dielectric, and dynamic properties of the simulated water, while maintaining manageable computational cost. With controlled and adjustable accuracy of the multiple-image charge representation of the reaction field, it is concluded that the employed model achieves convergence with only one image charge in the case of pure water. Future applications to pKa calculations, conformational sampling of solvated biomolecules and electrolyte solutions are briefly discussed.

The 3D structures of G-Quadruplexes of HIV-1 integrase inhibitors: molecular dynamics simulations in aqueous solution and in the gas phase

The unimolecular G-quadruplex structures of d(GGGTGGGTGGGTGGGT) (G1) and d(GTGGTGGGTGGGTGGGT) (G2) are known as the potent nanomolar HIV-1 integrase inhibitors, thus investigating the 3D structures of the two sequences is significant for structure-based rational anti-HIV drug design. In this research, based on the experimental data of circular dichroism (CD) spectropolarimetry and electrospray ionization mass spectrometry (ESI-MS), the initial models of G1 and G2 were constructed by molecular modeling method. The modeling structures of G1 and G2 are intramolecular parallel-stranded quadruplex conformation with three guanine tetrads. Particularly, the structure of G2 possesses a T loop residue between the first and the second G residues that are the component of two adjacent same-stranded G-tetrad planes. This structure proposed by us has a very novel geometry and is different from all reported G-quadruplexes. The extended (35 ns) molecular dynamic (MD) simulations for the models indicate that the G-quadruplexes maintain their structures very well in aqueous solution whether the existence of K(+) or NH (4) (+) in the central channel. Furthermore, we perform 500 ns MD simulations for the models in the gas phase. The results show that all the ion-G-quadruplex complexes are maintained during the whole simulations, despite the large magnitude of phosphate-phosphate repulsions. The gas phase MD simulations provide a good explanation to ESI-MS experiments. Our 3D structures for G1 and G2 will assist in understanding geometric formalism of G-quadruplex folding and may be helpful as a platform for rational anti-HIV drug design.

Hydrogen transfer and hydration properties of HnPO43−n (n=–3) in water studied by first principles molecular dynamics simulations

Density functional theory Perdew-Burke-Ernzerhof [Perdew et al., Phys. Rev. Lett. 77, 3865 (1996)] molecular dynamics simulations of aqueous solutions of orthophosphate species H(n)PO(4)(3-n) (n=0-3) provide new insights into hydrogen transfer and intermolecular and hydration properties of these important aqueous species. Extensive Car-Parrinello molecular dynamics simulations of the orthophosphate ion PO(4)(3-), of the hydrogen phosphate anions, HPO(4)(2-) and H(2)PO(4)(-), and of the orthophosphoric acid, H(3)PO(4), in explicit water show that the process of proton transfer from H(n)PO(4)(3-n) to the surrounding water molecules is very fast, less than 1 ps, and indicate that the dehydrogenation occurs through a concerted proton hopping mechanism, which involves H(n)PO(4)(3-n) and three water molecules. Analysis of the intermolecular H(n)PO(4)(3-n)-water structure shows that the PO(4)(3-) anions have a significant effect on the H-bonding network of bulk water and the presence of P-O(-) moieties induce the formation of new types of H-H interactions around this orthophosphate. Calculated probability distributions of the coordination numbers of the first hydration shell of PO(4)(3-), HPO(4)(2-), and H(2)PO(4)(-) show that these phosphate species display a flexible first coordination shell (between 7 and 13 water molecules) and that the flexibility increases on going from PO(4)(3-) to H(2)PO(4)(-). The strength and number of hydrogen bonds of PO(4)(3-), HPO(4)(2-), and H(2)PO(4)(-) are determined through a detailed analysis of the structural correlation functions. In particular, the H-bond interactions between the oxygen atoms of the phosphates and the surrounding water molecules, which decrease on going from PO(4)(3-) to the hydrogenated H(2)PO(4)(-) species, explain the diminished effect on the structure of water with the increasing hydrogenation of the orthophosphate anions.

Relation between Surface Tension and Ion Adsorption at the Air−Water Interface: A Molecular Dynamics Simulation Study

Classical molecular dynamics simulations of aqueous solutions of sodium chloride and potassium fluoride at two different concentrations have been carried out using polarizable force fields and standard additive force fields (not including polarizability explicitly). We show that the presence of chloride ions at the air-solution interface, as predicted from the polarizable simulations of NaCl solutions, is reconcilable with the classical thermodynamics results of Gibbs absorption theory. We discuss the role of system size in the establishment of a bulklike region in which the ion densities have converged to the same value. We compare the results for NaCl solutions with those obtained for KF at two concentrations. We find that the computed surface tension and the surface excess follow the experimental trend for each salt solution. We have characterized the extent of adsorption by calculating the fraction of the solution surface area that is occupied by each ion. The analysis reveals that, as expected, in the KF solution neither the cation nor the anion is present on the surface, regardless of whether or not a polarizable force field is employed. On the other hand, in the NaCl solutions, chloride anions occupy the surface to an extent that is roughly proportional to their bulk concentration, but only when a polarizable model is used.

Nanosecond molecular dynamics simulations of Cdc25B and its complex with a 1,4-naphthoquinone inhibitor: Implications for rational inhibitor design

Cdc25 phosphatases have been considered as attractive drug targets for anticancer therapies due to the correlation of their overexpression with a wide variety of cancers. To gain insight into designing new potent inhibitors, we investigate the dynamic properties of Cdc25B and its complex with a 1,4-naphtoquinone inhibitor NSC 95397 by means of molecular dynamics simulations in aqueous solution. It is shown from the calculated dynamic properties that the malleability of the residues 530–532 residing at the start of C-terminal region around the active site should be responsible for the catalytic action of Cdc25B. However, binding of the inhibitor in the active site leads to a substantial decrease in the motional amplitude of the flexible residues, due to the hydrophobic interactions with the side chain of Met531. The simulation results also indicate that at least four hydrogen bonds are involved in the enzyme-inhibitor complex. Among them, the hydrogen bond between the side chain carboxylate group of Glu478 and one of the hydroxyl groups of the inhibitor is found to be the most significant binding force stabilizing the inhibitor in the active site. This result supports the previous experimental implication that the possession of a single hydroxyl group is sufficient for the inhibitory activity of 1,4-naphthoquinone inhibitors.

Molecular Dynamics Studies of Side Chain Effect on the β-1,3-d-Glucan Triple Helix in Aqueous Solution

beta-1,3-D-glucans have been isolated from fungi as right-handed 6(1) triple helices. They are categorized by the side chains bound to the main triple helix through beta-(1-->6)-D-glycosyl linkage. Indeed, since a glucose-based side chain is water soluble, the presence and frequency of glucose-based side chains give rise to significant variation in the physical properties of the glucan family. Curdlan has no side chains and self-assembles to form an water-insoluble triple helical structure, while schizophyllan, which has a 1,6-D-glucose side chain on every third glucose unit along the main chain, is completely water soluble. A thermal fluctuation in the optical rotatory dispersion is observed for the side chain, indicating probable co-operative interaction between the side chains and water molecules. This paper documents molecular dynamics simulations in aqueous solution for three models of the beta-1,3-D-glucan series: curdlan (no side chain), schizophyllan (a beta-(1-->6)-D-glycosyl side-chain at every third position), and a hypothetical triple helix with a side chain at every sixth main-chain glucose unit. A decrease was observed in the helical pitch as the population of the side chain increased. Two types of hydrogen bonding via water molecules, the side chain/main chain and the side chain/side chain hydrogen bonding, play an important role in determination of the triple helix conformation. The formation of a one-dimensional cavity of diameter about 3.5 A was observed in the schizophyllan triple helix, while curdlan showed no such cavity. The side chain/side chain hydrogen bonding in schizophyllan and the hypothetical beta-1,3-D-glucan triple helix could cause the tilt of the main-chain glucose residues to the helix.

Molecular Simulation of the Hydration of Ethene to Ethanol Using Ab Initio Potentials and Free Energy Curves

Molecular dynamics simulations of aqueous solutions at infinite dilution of the reaction of water with ethene: H2O + CH2CH2 --> CH3CH2OH were performed using Lennard-Jones 12-6-1 potentials to describe the solute-solvent interactions, and TIP3P to describe the water-water interactions. The Morokuma decomposition scheme of ab initio interaction energies at the SCF level and the dispersion component at the MP2 level were used to reproduce the molecular parameters of the solute-water interaction potentials. The results show that the functions that use the EX-PL-DIS-ES interaction model to describe the solvation of the reactant, transition state, and product systems lead to good values of the reaction (Delta G) and acceptable values of the activation (Delta G#) free energy as compared with those from using AMBER-derived parameters, using the available theoretical and experimental data as referents.

Antitumor Activity, X-ray Crystal Structure, and DNA Binding Properties of Thiocoraline A, a Natural Bisintercalating Thiodepsipeptide

The marine natural product thiocoraline A displayed approximately equal cytotoxic activity at nanomolar concentrations in a panel of 12 human cancer cell lines. X-ray diffraction analyses of orthorhombic crystals of this DNA-binding drug revealed arrays of docked pairs of staple-shaped molecules in which one pendent hydroxyquinoline chromophore from each cysteine-rich molecule appears intercalated between the two chromophores of a facing molecule. This arrangement is in contrast to the proposed mode of binding to DNA that shows the two drug chromophores clamping two stacked base pairs, in agreement with the nearest-neighbor exclusion principle. Proof of DNA sequence recognition was obtained from both classical DNase I footprinting experiments and determination of the melting temperatures of several custom-designed fluorescently labeled oligonucleotides. A rationale for the DNA-binding behavior was gained when models of thiocoraline clamping a central step embedded in several octanucleotides were built and studied by means of unrestrained molecular dynamics simulations in aqueous solution.

Refinement of the AMBER Force Field for Nucleic Acids: Improving the Description of α/ γ Conformers

We present here the parmbsc0 force field, a refinement of the AMBER parm99 force field, where emphasis has been made on the correct representation of the α/ γ concerted rotation in nucleic acids (NAs). The modified force field corrects overpopulations of the α/ γ = (g+,t) backbone that were seen in long (more than 10 ns) simulations with previous AMBER parameter sets (parm94-99). The force field has been derived by fitting to high-level quantum mechanical data and verified by comparison with very high-level quantum mechanical calculations and by a very extensive comparison between simulations and experimental data. The set of validation simulations includes two of the longest trajectories published to date for the DNA duplex (200 ns each) and the largest variety of NA structures studied to date (15 different NA families and 97 individual structures). The total simulation time used to validate the force field includes near 1 μs of state-of-the-art molecular dynamics simulations in aqueous solution.

Dynamics of Water in Solvation Shells and Intersolute Regions of C60: A Molecular Dynamics Simulation Study

We present dynamical characteristics of the solvent in various solvation shells of a C60 molecule as well as intersolute region between two fullerene molecules. Results are obtained from extensive atomistic molecular dynamics simulations of aqueous solutions of C60 in the isothermal−isobaric ensemble. Information about translational mobilities of water in and around fullerene molecules are obtained from velocity auto correlation function and mean square displacements as calculated from simulation data. Reorientational behavior also is investigated by analyzing first and second rank dipole−dipole correlation functions as calculated from simulation trajectories. Both the translational and rotational mobilities of water in the first solvation shell around a C60 molecule are found to be much slower than the same in the second and third solvation shells. Slower decay of the occupation time correlation function for the water in the first hydration shell indicates slower exchange of these water molecules with th...

Stereoselectivity by Enantiomeric Inhibitors of Matrix Metalloproteinase-8: New Insights from Molecular Dynamics Simulations

Molecular Dynamics simulations in aqueous solution were performed for the matrix metalloproteinase-8 (MMP-8) free catalytic domain and for its complexes with the (R)- and (S)-[1-(4'-methoxybiphenyl-4-sulfonylamino)-2-methylpropyl] phosphonate. The 144-155 loop of the enzyme undergoes a drastic decrease of mobility once complexed with both enantiomers. The two enantiomers induce a different decrease of conformational entropy upon complexation. The higher affinity of the R-enantiomer can be related to the lower loss of conformational entropy accompanying its binding. The differences in the dynamical behavior of the protein induced by the two enantiomers are discussed at molecular level and the mode of binding of the simulated complexes is compared with that previously determined by X-ray crystallography.