Investigation of Lignin-water interactions by molecular simulation

The results of molecular dynamics simulations of three lignin-water systems are presented. Static and dynamic properties of each system are compared to a benchmark system consisting entirely of water molecules. The significantly reduced mobility of water molecules local to lignin hydroxyl regions is attributed to hydrogen bond formation, while the slightly reduced mobility of water molecules in the vicinity of lignin methoxyl groups results from a hydrophobic effect that causes water molecules to structure themselves around these groups. The average diffusion of water in each system correlates with the number of methoxyl groups present in the system. As the number of methoxyls in the system increases, so too does the average diffusion constant of water in that system. The bulky methoxyl groups obstruct water from accessing lignin hydroxyl regions where hydrogen bond formation is anticipated and the hydrogen-bonded water lowers the average diffusion constant.     

Structural details of urea binding to barnase: a molecular dynamics analysis.

BACKGROUND: The molecular mechanism of urea-induced protein unfolding has not been established. It is generally thought that denaturation results from the stabilizing interactions of urea with portions of the protein that are buried in the native state and become exposed upon unfolding of the protein. RESULTS: We have performed molecular dynamics simulations of barnase (a 110 amino acid RNase from Bacillus amyloliquefaciens) with explicit water and urea molecules at 300 K and 360 K. The native conformation was unaffected in the 300 K simulations at neutral and low pH. Two of the three runs at 360 K and low pH showed some denaturation, with partial unfolding of the hydrophobic core 2. The first solvation shell has a much higher density of urea molecules (water/urea ratio ranging from 2.07 to 2.73) than the bulk (water/urea ratio of 4.56). About one half of the first-shell urea molecules are involved in hydrogen bonds with polar or charged groups on the barnase surface, and between 15% and 18% of the first-shell urea molecules participate in multiple hydrogen bonds with barnase. The more stably bound urea molecules tend to be in crevices or pockets on the barnase surface. CONCLUSIONS: The simulation results indicate that an aqueous urea solution solvates the surface of a polypeptide chain more favorably than pure water. Urea molecules interact more favorably with nonpolar groups of the protein than water does, and the presence of urea improves the interactions of water molecules with the hydrophilic groups of the protein. The results suggest that urea denaturation involves effects on both nonpolar and polar groups of proteins.     

Molecular dynamics simulation study for diffusion of Na+ ion in water-filled carbon nanotubes at 25°C

We present results of molecular dynamics simulations for diffusion of Na⁺ ion in water-filled carbon nanotubes (CNTs) at 25°C using the extended simple point charge water potential. Simulation results indicate the general trend that the diffusion coefficients of Na⁺ ion and water molecule in CNTs decrease with an increase in water density and are larger than those in the bulk solution. The average potential energies of ion–water and water–water, the radial distribution functions, the hydration numbers and the residence times of the hydrated water molecules are discussed. The classical solventberg picture describes Na⁺ ion in water adequately for systems with the small values of diffusion coefficients.     

Biomembrane simulations of 12 lipid types using the general amber force field in a tensionless ensemble

The AMBER family of force fields is one of the most commonly used alternatives to describe proteins and drug-like molecules in molecular dynamics simulations. However, the absence of a specific set of parameters for lipids has been limiting the widespread application of this force field in biomembrane simulations, including membrane protein simulations and drug-membrane simulations. Here, we report the systematic parameterization of 12 common lipid types consistent with the General Amber Force Field (GAFF), with charge-parameters determined with RESP at the HF/6–31G(d) level of theory, to be consistent with AMBER. The accuracy of the scheme was evaluated by comparing predicted and experimental values for structural lipid properties in MD simulations in an NPT ensemble with explicit solvent in 100:100 bilayer systems. Globally, a consistent agreement with experimental reference data on membrane structures was achieved for some lipid types when using the typical MD conditions normally employed when handling membrane proteins and drug-membrane simulations (a tensionless NPT ensemble, 310?K), without the application of any of the constraints often used in other biomembrane simulations (such as the surface tension and the total simulation box area). The present set of parameters and the universal approach used in the parameterization of all the lipid types described here, as well as the consistency with the AMBER force field family, together with the tensionless NPT ensemble used, opens the door to systematic studies combining lipid components with small drug-like molecules or membrane proteins and show the potential of GAFF in dealing with biomembranes.     

Electrodissociation of clathrate-like structures

In the present work, we develop molecular dynamics (MD) simulations in the NPT (isobaric–isothermic) ensemble to analyse the effect of an external electrostatic field over a cubic methane hydrate crystallite. The amplitude of the field is in the range 0.5–3.0 V/nm. For the simulations, we used the SPC/E rigid water model and a single-site model for methane at a temperature of 248 K and a pressure of 20 bar. When the external electrostatic field is applied, the water dipoles are oriented in such a way that the methane molecules can diffuse far away from the water cages, hence the clathrate dissociation takes place. This last phenomenon was observed for intensities above 1.5 V/nm. Taking the final configuration of each run as input, we develop a new set of MD simulations, and we observe that the stable clathrate is not recovered immediately when the external electrostatic field is turned off due to limitations in the simulation time.     

Molecular dynamics simulations of urea and thermal-induced denaturation of S-peptide analogue

Molecular dynamics simulations of the S-peptide analogue AETAAAKFLREHMDS in water at 278 and 358 K, and in 8 M urea at 278 K were performed. The results show agreement with experiments. The helix is stable at low temperature (278 K), while at 358 K, unfolding is observed. The effects of urea on protein stability have been studied. The data support a model in which urea denatures proteins by: (1) diminishing the hydrophobic effect by displacing water molecules from the solvent shell around nonpolar groups; and (2) binding directly to amide units (NH and CO groups) via hydrogen bonds. The results of cluster analysis and essential dynamics analysis suggest that the mechanism of urea and thermal-induced denaturation may not be the same.     

Modelling Diffusion in Zeolites by Molecular Dynamics Simulations

Abstract

The diffusion of molecules sorbed in zeolites is of growing interest for understanding the mechanisms of chemical processes with regard to selectivity and reactivity [1].

MD simulations give insight into physical systems on the molecular level allowing to study and visualize the motion of molecules even beyond the possibilities of experiments [2,3]. Single system parameters can easily be varied to study their influence, also those parameters that are fixed in reality (e.g., the size of particles). We present a cross section of our recent work to illustrate the capabilities of MD: The self diffusion coefficients (D) of a mixture of methane and xenon in silicalite show remarkable deviations from those of the pure species. This is shown and confirmed by PFG NMR experiments [4].

Simulating ethane in zeolite A the mechanism of diffusion has been studied. The effects of rotation on the diffusion lead to cases where D decreases with growing temperature [5].

The independence of self diffusion on lattice vibrations is proven even for zeolites with windows of guest particle size comparing simulations with rigid and vibrating zeolite lattice [6].     

Preparative fractionation of lignin by gel-permeation chromatography

The combination of an agarose gel (Bio-Gel A) and a dioxane–water (1:1) solvent system allowed the fractionation, on a preparative scale, of a very polydisperse, non-derivatized lignin preparation (enzymatically liberated lignin prepared from sweetgum sapwood with Lenzites trabea). Three fractions differing markedly in molecular weight were obtained. A gel of crosslinked alkylated dextran (Sephadex LH-20) with the same solvent system allowed division of the lowest molecular weight fraction into two fractions. These materials were characterized by measurements of intrinsic viscosity and number-average molecular weights in dimethylformamide and dioxane–water. It was established that the two highest molecular weight fractions were associated in an average trimeric form in dioxane-water (1:1) as compared to the form (considered to be molecular) that occurred in dimethylformamide. Molecular size distributions and eluant volumes of the fractions were determined with a Sephadex G-100–formamide system, the latter being one of the most powerful nonaqueous solvents for lignin. Adsorption effects were known to be absent in this case, and the lignin molecules were considered to be unassociated in formamide. The four fractions were distinguishable with the formamide–G-100 system, thus indicating that the original fractionation was based on molecular size. The enzymatically liberated lignin contained molecules that comprised a continuum of molecular weights from approximately monomeric to molecules that were at the limit of the solvating power of dioxane–water (1:1) and dimethylformamide. Limited physicochemical data were consistent with a compact, approximately spherically symmetric shape of the lignin in solution.     

Protective mechanisms of α,α-trehalose revealed by molecular dynamics simulations

Molecular dynamics simulations were carried out to model aqueous solution with different concentration of α,α-trehalose, one kind of non-reducing sugars possessing outstanding freeze-drying protective effect on biological system. The dihedral angles of the intraglycosidic linkage in trehalose were measured to estimate its structure rigidity. The dynamics and hydrogen bonding properties were studied by calculating the self-diffusion coefficient of trehalose and the distributions and lifetimes of various types of H-bonds in the solution. Through analysing the results as well as comparison with another common sugar sucrose, the freeze-drying protective mechanism of trehalose was explained at molecule level. First, trehalose is able to maintain the local structure around it as a frame due to its relatively rigid conformation. Second, the addition of trehalose restrains the water molecules from rearrangement as a result of low mobility, thus reduces the probability of freezing; trehalose has lower diffusion coefficient than water and bigger thermal diffusivity, which are favourable for vitrification. Third, the formation of H-bonds between trehalose and water and between trehalose molecules is the essence of the protective effect. Trehalose does not work via strengthening the H-bonds formed between water molecules (W–W H-bonds), instead of which it breaks the potential tetrahedral pattern of W–W H-bonds, thus suppresses the tendency of ice formation. It was also found that trehalose realises protective action better at higher concentration as far as this study is concerned.     

Investigating the effects of wettability and gaseous nanobubbles on roughened wall–fluid interface using molecular dynamics simulation

This paper reports on the use of molecular dynamics (MD) simulation to investigate the coupling effects of wettability, surface roughness and interfacial nanobubbles (INBs) on wall–fluid interfaces. The fluid properties close to the wall–fluid interface, such as potential energy, density, diffusion coefficients of fluid molecules and effective slip length are simulated. In the cases without surface nanobubbles, regions with lower potential energy have a higher probability of hosting water molecules. The local translational and rotational diffusion coefficients of water within the cavities are strongly influenced by wettability but largely unaffected by hydrodynamic effects. In cases where INBs exist, variations in wettability result in distinctly different argon morphologies. Argon nanobubbles form a convex shape on Wenzel-like interfaces but a shallow concave shape on Cassie-like interfaces. The phenomenon of water molecules invading grooves tends to occur on Wenzel-like interfaces; however, this depends largely on the morphology of the grooves. The high mobility and high density of argon molecules indicate that the state of the argon molecules within the grooves may require further investigation. Our results also show that the effective slip length is significantly influenced by wall–fluid wettability as well as the morphology of INBs.     

Characterization of the denaturation of human alpha-lactalbumin in urea by molecular dynamics simulations

Molecular dynamics (MD) simulations were used to characterize the non-cooperative denaturation of the molten globule A-state of human alpha-lactalbumin by urea. A solvent of explicit urea and water molecules was used, corresponding to a urea concentration of approximately 6M. Three simulations were performed at temperatures of 293K, 360K and 400K, with lengths of 2 ns, 8 ns and 8 ns respectively. The results of the simulations were compared with experimental data from NMR studies of human alpha-lactalbumin and related peptides. During the simulations, hydrogen bonds were formed from the protein to both urea and water molecules as intra-protein hydrogen bonds were lost. Urea was shown to compete efficiently with water as both a hydrogen bond donor and acceptor. Radial distribution functions of water and urea around hydrophobic side chain atoms showed a significant increase in urea molecules in the solvation shell as the side chains became exposed during denaturation. A considerable portion of the native-like secondary structure persisted throughout the simulations. However, in the simulations at 360K and 400K, there were substantial changes in the packing of aromatic and other hydrophobic side chains in the protein, and many native contacts were lost. The results suggest that during the non-cooperative denaturation of the molten globule, secondary structure elements are stabilized by non-specific, non-native interactions.     

Grand canonical ensemble Monte Carlo simulation of the dCpG/proflavine crystal hydrate.

The grand canonical ensemble Monte Carlo molecular simulation method is used to investigate hydration patterns in the crystal hydrate structure of the dCpG/proflavine intercalated complex. The objective of this study is to show by example that the recently advocated grand canonical ensemble simulation is a computationally efficient method for determining the positions of the hydrating water molecules in protein and nucleic acid structures. A detailed molecular simulation convergence analysis and an analogous comparison of the theoretical results with experiments clearly show that the grand ensemble simulations can be far more advantageous than the comparable canonical ensemble simulations.     

The influence of nicotine on pioglitazone encapsulation into carbon nanotube: the investigation of molecular dynamic and density functional theory

In this work, molecular dynamics simulations of the insertion of pioglitazone into the nanotube with chirality (10, 10) at 400 K and 1 bar in the presence and absence of nicotine molecules and in different drug concentrations have been studied. The main aim is consideration of the effect of nicotine in the drug encapsulation process. The results indicate that encapsulation of pioglitazone could be attributed to the water flow via van der Waals and hydrophilic interactions. Because of the existence of the partial π–π interactions between aromatic rings of pioglitazone and the conjugated aromatic rings of nanotube, pioglitazone molecule can enter inside the nanotube. Some physical properties such as hydrogen bonding, number of contacts, also, the diffusion coefficient of the pioglitazone and water molecules, and variation of the center of mass have been calculated during the simulation. Furthermore, computing the electronic structure has also been done on model systems for quantitative determination of the adsorption energy (E_ads). The B3LYP/6-31G* level calculations on four different configurations of pioglitazone/carbon nanotube (CNT) and nicotine/CNT show that the interaction of drug with the inside of the nanotube is stronger than the other forms.     

Salting-in of neopentane in the aqueous solutions of urea and glycine-betaine

The effects of urea and glycine-betaine (GB) osmolytes on the hydrophobic interactions of neopentane in water have been studied using molecular dynamics simulations. From the study of the potentials of mean force, it is observed that both urea and GB decrease the association and solvation of neopentane. The calculated equilibrium constants show that urea and GB decrease the population of solvent-separated minima of neopentane. The hydrophobic association as well as solvation of neopentane molecules are stabilised by entropy and enthalpy in the mixtures. The radial distribution functions (RDFs) and running coordination numbers of water, urea and GB molecules show that neopentane shows salting-in behaviour in aqueous-GB, aqueous-urea and aqueous-urea-GB mixtures. Neopentane is preferentially solvated by GB in aqueous-GB and preferentially solvated by urea in aqueous-urea-GB solutions. The preferential solvation of neopentane by GB suggests that GB decreases the interaction between neopentane molecules i.e. salting-in of neopentane. The calculated solvation free energies and radial density profiles of neopentane also support the salting-in behaviour of neopentane in the mixtures of these osmolytes.     

Mean field analysis of FKBP12 complexes with FK506 and rapamycin: Implications for a role of crystallographic water molecules in molecular recognition and specificity

Mean field analysis of FKBP12 complexes with FK506 and rapamycin has been performed by using structures obtained from molecular docking simulations on a simple, yet robust molecular recognition energy landscape. When crystallographic water molecules are included in the simulations as an extension of the FKBP12 protein surface, there is an appreciable stability gap between the energy of the native FKBP12–FK506 complex and energies of conformations with the “native-like” binding mode. By contrast, the energy spectrum of the FKBP12–rapamycin complex is dense regardless of the presence of the water molecules. The stability gap in the FKBP12–FK506 system is determined by two critical water molecules from the effector region that participate in a network of specific hydrogen bond interactions. This interaction pattern protects the integrity and precision of the composite ligand-protein effector surface in the binary FKBP12–FK506 complex and is preserved in the crystal structure of the FKBP12–FK506–calcineurin ternary complex. These features of the binding energy landscapes provide useful insights into specific and nonspecific aspects of FK506 and rapamycin recognition. Proteins 28:313–324, 1997. © 1997 Wiley-Liss, Inc.     

Coarse-grained modelling of urea-adamantyl functionalised poly(propylene imine) dendrimers

To investigate the behaviour of poly(propylene imine) dendrimers – and urea–adamantyl functionalised ones – in solution using molecular dynamics simulations, we developed a coarse-grained model to tackle the relatively large system sizes and time scales needed. Harmonic bond and angle potentials were derived from atomistic simulations using an iterative Boltzmann inversion scheme, modified to incorporate Gaussian fits of the bond and angle distributions. With the coarse-grained model and accompanying force field simulations of generations 1–7 of both dendrimer types in water were performed. They compare favourably with atomistic simulations and experimental results on the basis of size, shape, monomer density, spacer back-folding and atomic form factor measurements. These results show that the structural dynamics of these dendrimers originate from flexible chains constrained by configurational and spatial requirements. Large dendrimers are more rigid and spherical, while small ones are flexible, alternatively rod-like and globular.     

Comparative prediction of binding affinity of Hydroxyurea anti-cancer to boron nitride and carbon nanotubes as smart targeted drug delivery vehicles

Abstract

In this study, the adsorption of Hydroxyurea (HU) onto the inner and outer surfaces of boron nitride and carbon nanotubes (CNTs) was investigated using the density functional theory calculations and molecular dynamics (MDs) simulations in aqueous solution. The values of the adsorption energy show that HU molecule is preferentially adsorbed inside of boron nitride and CNTs with the molecular axis parallel to the tubes axis, which means that the cavity of nanotubes is favorable for encapsulation of this drug. Also, it was found that the HU/boron nitride nanotube (BNNT) system is more stable than the HU/CNT system. The stability of the complexes of HU/ BNNT attributed to the formation of the intermolecular hydrogen bonds between the H atoms of HU molecule and the N atoms of BNNT, which is confirmed by Bader’s quantum theory of atoms in molecules. The natural bond orbital analysis shows the charge transfers occur from HU molecule to nanotubes in all complexes. Moreover, the adsorption of HU molecule on the surfaces of the nanotubes was investigated by explicit water models. Also, the adsorption behavior of HU on the functionalized boron nitride and CNTs is investigated to design and develop new nanocarriers for biomedical applications. Furthermore, MDs simulations are examined in the presence of one and two drug molecules. The obtained results illustrate that the lowest value of Lennard–Jones (L–J) energy between drug and nanotubes exist in the simulation system with two drug molecules.     

Gibbs ensemble Monte Carlo simulations of binary vapour–liquid–liquid equilibrium: application to n-hexane–water and ethane–ethanol systems

Gibbs ensemble Monte Carlo (GEMC) simulations in the isochoric–isothermal (NVT) ensemble were used to simulate vapour–liquid–liquid equilibrium (VLLE) for binary n-hexane–water and ethane–ethanol mixtures. The GEMC simulation of binary VLLE data proved to be extremely difficult and that is probably the reason why the open literature is so sparse with simulations for these types of systems. The results presented in this paper are to our knowledge the first successful binary three-phase GEMC simulations of non-idealised fluid systems. This paper also shows that the isobaric–isothermal (NPT) ensemble is unsuitable for the simulation of phase equilibria of binary three-phase systems.     

Modeling the accessible conformations of the intrinsically unstructured transactivation domain of p53

Internuclear distances derived from paramagnetic relaxation enhancement (PRE) data were used to restrain molecular dynamics simulations of the intrinsically unstructured transactivation domain of the tumor suppressor protein, p53. About 1000 structures were simulated using ensemble averaging of replicate molecules to compensate for the inherent bias in the PRE-derived distances. Gyration radii measurements on these structures show that the p53 transactivation domain (p53TAD) is statistically predominantly in a partially collapsed state that is unlike the open structure that is found for p53TAD bound to either the E3 ubiquitin ligase, MDM2, or the 70 kDa subunit of replication protein A, RPA70. Contact regions that potentially mediate the collapse were identified and found to consist of mostly hydrophobic residues. The identified contact regions preferentially place the MDM2 and RPA70 binding regions in close proximity. We show that our simulations thoroughly sample the available range of conformations and that a fraction of the molecules are in an open state that would be competent for binding either MDM2 or RPA70. We also show that the Stokes radius estimated from the average gyration radius of the ensemble is in good agreement with the value determined using size exclusion chromatography. Finally, the presence of a persistent loop localized to a PXP motif was identified. Serine residues flanking the PXP motif become phosphorylated in response to DNA damage, and we postulate that this will perturb the equilibrium population to more open conformations.     

Effect of frictional force on urea and thiourea during an intramembrane transport: an explicit solvent Langevin dynamics simulation method

An explicit solvent Langevin dynamics (LD) simulation method is employed to investigate the effect of frictional force on the solute–solvent interactions in urea and thiourea, which are subjected to varied degree of frictional forces akin to diffusional transport across the membrane system. Utilizing the frictional force concept in LD method, the effect of increasing frictional coefficient is studied on the microscopic properties such as single-point energy and N–C–N bond angle of urea and thiourea in aqueous solutions. The present work follows a self-conscious approach by explicitly including the solvent molecules in the LD simulations. The results are further compared with the standard Langevin approach without explicitly specifying solvent molecules. An analysis of the results reveals that the two cases differ strongly in the intermediate (Brownian) regime of frictional coefficient.