Molecular switch triggered by solvent polarity: synthesis,Acid-base behavior,alkali metal ion complexation,and crystal structure

The synthesis and characterization of the new tetraazamacrocycle L, bearing two 1,1'-bis(2-phenol) groups as side-arms, is reported. The basicity behavior and the binding properties of L toward alkali metal ions were determined by means of potentiometric measurements in ethanol/water 50:50 (v/v) solution (298.1+/-0.1 K, I=0.15 mol dm(-3)). The anionic H(-1)L(-) species can be obtained in strong alkaline solution, indicating that not all of the acidic protons of L can be removed under the experimental conditions used. This species behaves as a tetraprotic base (log K(1)=11.22, log K(2)=9.45, log K(3)=7.07, log K(4)=5.08), and binds alkali metal ions to form neutral [MH(-1)L] complexes with the following stability constants: log K(Li)=3.92, log K(Na)=3.54, log K(K)=3.29, log K(Cs)=3.53. The arrangement of the acidic protons in the H(-1)L(-) species depends on the polarity of the solvents used, and at least one proton switches from the amine moiety to the aromatic part upon decreasing the polarity of the solvent. In this way two different binding areas, modulated by the polarity of solvents, are possible in L. One area is preferred by alkali metal ions in polar solvents, the second one is preferred in solvents with low polarity. Thus, the metal ion can switch from one location to the other in the ligand, modulated by the polarity of the environment. A strong hydrogen-bonding network should preorganize the ligand for coordination, as confirmed by MD simulations. The crystal structure of the [Na(H(-1)L)].CH(3)CN complex (space group P2(1)/c, a=12.805(1), b=20.205(3), c=14.170(2) A, beta=100.77(1) degrees, V=3601.6(8) A(3), Z=4, R=0.0430, wR2=0.1181), obtained using CH(2)Cl(2)/CH(3)CN as mixed solvent, supports this last aspect and shows one of the proposed binding areas.     

Influence of temperature, friction, and random forces on folding of the B-domain of staphylococcal protein A: all-atom molecular dynamics in implicit solvent

The influences of temperature, friction, and random forces on the folding of protein A have been analyzed. A series of all-atom molecular dynamics folding simulations with the Amber ff99 potential and Generalized Born solvation, starting from the fully extended chain, were carried out for temperatures from 300 to 500 K, using (a) the Berendsen thermostat (with no explicit friction or random forces) and (b) Langevin dynamics (with friction and stochastic forces explicitly present in the system). The simulation temperature influences the relative time scale of the major events on the folding pathways of protein A. At lower temperatures, helix 2 folds significantly later than helices 1 and 3. However, with increasing temperature, the folding time of helix 2 approaches the folding times of helices 1 and 3. At lower temperatures, the complete formation of secondary and tertiary structure is significantly separated in time whereas, at higher temperatures, they occur simultaneously. These results suggest that some earlier experimental and theoretical observations of folding events, e.g., the order of helix formation, could depend on the temperature used in those studies. Therefore, the differences in temperature used could be one of the reasons for the discrepancies among published experimental and computational studies of the folding of protein A. Friction and random forces do not change the folding pathway that was observed in the simulations with the Berendsen thermostat, but their explicit presence in the system extends the folding time of protein A.     

Revisiting the structure and dynamics of hydrated Cd2+ in aqueous solutions: Insights from the RI-SCS-MP2/MM molecular dynamics simulation

The spin component scale MP2/molecular mechanics molecular dynamics simulation investigated the hydration shell formation and hydrated Cd²⁺ dynamics in the water environment. At the first hydration shell, six water molecules with 2.27 Å for the average distance between water and Cd²⁺. Dynamical properties were analyzed by computing the water molecule's mean residence time (MRT) in its first and second hydration shells. The MRT of each shell was determined to be 31.8 and 1.92 ps, suggesting the strong influence of Cd²⁺ in the first hydration shell. The second shell was labile, with an average number of water molecules being 18. Despite the strong interaction between Cd²⁺ and water molecules in the first shell, the influence of ions in the second hydration shell remained weak.     

Transformation between α‐helix and β‐sheet structures of one and two polyglutamine peptides in explicit water molecules by replica‐exchange molecular dynamics simulations

Aggregation of polyglutamine peptides with β‐sheet structures is related to some important neurodegenerative diseases such as Huntington's disease. However, it is not clear how polyglutamine peptides form the β‐sheets and aggregate. To understand this problem, we performed all‐atom replica‐exchange molecular dynamics simulations of one and two polyglutamine peptides with 10 glutamine residues in explicit water molecules. Our results show that two polyglutamine peptides mainly formed helix or coil structures when they are separated, as in the system with one‐polyglutamine peptide. As the interpeptide distance decreases, the intrapeptide β‐sheet structure sometimes appear as an intermediate state, and finally the interpeptide β‐sheets are formed. We also find that the polyglutamine dimer tends to form the antiparallel β‐sheet conformations rather than the parallel β‐sheet, which is consistent with previous experiments and a coarse‐grained molecular dynamics simulation. © 2014 Wiley Periodicals, Inc.     

Study on growth rate of TiO2 nanostructured thin films: simulation by molecular dynamics approach and modeling by artificial neural network

Effects of the deposition process parameters on the thickness of TiO₂ nanostructured film were simulated using the molecular dynamics (MD) approach and modeled by the artificial neural network (ANN) and regression method. Accordingly, TiO₂ nanostructured film was prepared experimentally with the sol–gel dip‐coating method. Structural instabilities can be expected, due to short‐ and/or long‐range intermolecular forces, leading to the surface inhomogeneities. In the MD simulation, the Morse potential function was used for the inter‐atomic interactions, and equations of motion for atoms were solved by Verlet algorithm. The effect of the withdrawal velocity, drying temperature and number of deposited layers were studied in order to characterize the film thickness. The results of MD simulations are reasonably consistent with atomic force microscopy, scanning electron microscopy and Dektak surface profiler. Finally, the outputs from experimental data were analyzed by using the ANN in order to investigate the effects of deposition process parameters on the film thickness. In this case, various architectures have been checked using 75% of experimental data for training of the ANN. Among the various architectures, feed‐forward back‐propagation network with trainer training algorithm was found as the best architecture. Based on the R‐squared value, the ANN is better than the regression model in predicting the film thickness. The statistical analysis for those results was then used to verify the fitness of the complex process model. Based on the results, this modeling methodology can explain the characteristics of the TiO₂ nanostructured thin film and growth mechanism varying with process conditions. © 2013 The Authors. Surface and Interface Analysis published by John Wiley & Sons Ltd.     

The influence of lateral and terminal substitution on the structure of a liquid crystal dendrimer in nematic solution: A computer simulation study

The choice of lateral and terminal substitution can have a major influence on the structure of a liquid crystalline supermolecule, which in turn can induce radically different phase behaviour. In this study we use molecular dynamics simulations to investigate the shape of a liquid crystal dendrimer within a liquid crystalline solvent. A coarse-grained (CG) simulation model is employed to represent a third generation dendrimer in which 32 mesogenic groups are bonded to chains at the end of each branch of the dendrimer. In this CG-model the liquid crystal groups can be appended either terminally or laterally. This bonding option is used to generate the structure of four separate systems: (a) a dendrimer with 32 terminal mesogens, (b) a dendrimer with 32 laterally appended mesogens, (c) and (d) dendrimers with 16 lateral and 16 terminal groups represented with laterally bonded sites on one side of the molecule, model (c) or next to terminally bonded sites, model (d). The simulations show that the dendrimer is able to change shape in response to molecular environment and that the molecular shape adopted depends critically on the nature of the lateral/terminal susbstitution.     

Effect of the environment on the stability of surfactant–polypeptide self‐assembled complexes: Molecular dynamics simulations of stoichiometric complexes formed by N‐dodecyltrimethylammonium and poly(α,L‐glutamate) in chloroform,methanol, and water

A series of molecular dynamics simulations have been performed to study the supramolecular structure of self‐assembled complexes formed by N‐dodecyltrimethylammonium cations and the synthetic polypeptide poly(α,L ‐glutamate). The influence of the type of solvent has been investigated, considering explicit environments of chloroform, water, and methanol on a stoichiometric complex containing 15 residues. In chloroform, the complex stabilizes in a regular structure: the polypeptide adopts an α‐helix conformation that is regularly surrounded by surfactant molecules to form electrostatic interactions through a multiple interaction pattern. However, this structure destabilizes in methanol and water: (a) the α‐helix unfolds in the two solvents and (b) the electrostatic links between the surfactant molecules and the polyanion are disrupted in aqueous solution, although these interactions are still preserved in methanol. The role of the solvent environment in stabilizing or destabilizing the polypeptide secondary structure, the organization of the surfactant molecules, and predominantly the surfactant–polypeptide supramolecular organization is discussed in detail. © 2006 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 44: 1122–1133, 2006     

The influence of lateral and terminal substitution on the structure of a liquid crystal dendrimer in nematic solution: A computer simulation study

The choice of lateral and terminal substitution can have a major influence on the structure of a liquid crystalline supermolecule, which in turn can induce radically different phase behaviour. In this study we use molecular dynamics simulations to investigate the shape of a liquid crystal dendrimer within a liquid crystalline solvent. A coarse‐grained (CG) simulation model is employed to represent a third generation dendrimer in which 32 mesogenic groups are bonded to chains at the end of each branch of the dendrimer. In this CG‐model the liquid crystal groups can be appended either terminally or laterally. This bonding option is used to generate the structure of four separate systems: (a) a dendrimer with 32 terminal mesogens, (b) a dendrimer with 32 laterally appended mesogens, (c) and (d) dendrimers with 16 lateral and 16 terminal groups represented with laterally bonded sites on one side of the molecule, model (c) or next to terminally bonded sites, model (d). The simulations show that the dendrimer is able to change shape in response to molecular environment and that the molecular shape adopted depends critically on the nature of the lateral/terminal susbstitution.     

Investigation of the solvent effect,molecular structure,electronic properties and adsorption mechanism of Tegafur anticancer drug on Graphene nanosheet surface as drug delivery system by molecular dynamics simulation and density functional approach

To understanding the adsorption mechanism and the induced effects of an anticancer drug, Tegafur molecule, on the surface of Graphene nanosheet (GNS) as a drug delivery system, we have performed density functional theory (DFT) and molecular dynamics (MD) methods. DFT calculations give valuable information on the structure, orientation, adsorption energy and charge transfer of nanosheet-molecule in the equilibrium GNS-Tegafur complexes in the gas phase as well as in the aqueous phase, i.e., water. The optimization of GNS-Tegafur geometries shows that drug molecule tends to adsorb via its six-membered aromatic ring to the hexagonal ring of Graphene nanosheet by π–π stacking interaction at the most stable physisorption configuration. Furthermore, the calculated solvation energy (E_sol) represented by a polarizable continuum model show the significant increase in the solubility of GNS after drug adsorption on its surface in the presence of H₂O solvent which leading to the possible applications of GNS in the drug delivery systems. MD simulation is also used to determine the effect of drug concentrations on dynamic properties of Tegafur adsorption on the GNS surfaces in the solution phase. Based on the obtained MD results, it is found that by increasing drug concentration, the van der Waals (vdW) interaction energy becomes more negative and the stabilities of the simulated complexes increase.     

Uranyl coordination in ionic liquids: the competition between ionic liquid anions, uranyl counterions, and Cl- anions investigated by extended X-ray absorption fine structure and UV-visible spectroscopies and molecular dynamics simulations

The first coordination sphere of the uranyl cation in room-temperature ionic liquids (ILs) results from the competition between its initially bound counterions, the IL anions, and other anions (e.g., present as impurities or added to the solution). We present a joined spectroscopic (UV-visible and extended X-ray absorption fine structure)-simulation study of the coordination of uranyl initially introduced either as UO2X2 salts (X-=nitrate NO3-, triflate TfO-, perchlorate ClO4-) or as UO2(SO4) in a series of imidazolium-based ILs (C4mimA, A-=PF6-, Tf2N-, BF4- and C4mim=1-methyl-3-butyl-imidazolium) as well as in the Me3NBuTf2N IL. The solubility and dissociation of the uranyl salts are found to depend on the nature of X- and A-. The addition of Cl- anions promotes the solubilization of the nitrate and triflate salts in the C4mimPF6 and the C4mimBF4 ILs via the formation of chloro complexes, also formed with other salts. The first coordination sphere of uranyl is further investigated by molecular dynamics (MD) simulations on associated versus dissociated forms of UO2X2 salts in C4mimA ILs as a function of A- and X- anions. Furthermore, the comparison of UO2Cl(4)2-, 2 X- complexes with dissociated X- anions, to the UO2X2, 4 Cl- complexes with dissociated chlorides, shows that the former is more stable. The case of fluoro complexes is also considered, as a possible result of fluorinated IL anion's degradation, showing that UO2F42- should be most stable in solution. In all cases, uranyl is found to be solvated as formally anionic UO2XnAmClp2-n-m-p complexes, embedded in a cage of stabilizing IL imidazolium or ammonium cations.     

Temperature effects on the structure and dynamics of liquid dimethyl sulfoxide: A molecular dynamics study

The molecular dynamics (MD) simulation technique has been employed to investigate the thermodynamic properties and transport coefficients of the neat liquid dimethyl sulfoxide (DMSO). The fluid has been studied at temperatures in the range 298–353 K and at a pressure equal to 1 atm. The simulations employed a nine-site potential model, which is presented for the first time here, and all the available non-polarizable models. The performance of each model is tested using the same statistical mechanical ensemble and simulation method under the same conditions, revealing its weaknesses and strengths. Thermodynamic properties, microscopic structure and dynamic properties, such as transport coefficients, rotational and single-dipole correlation times have been calculated and compared with available experimental results. Estimations of transport coefficients from various theoretical and empirical models are tested against experimental and MD results. Translational and rotational dynamics suggest the existence of the cage effect and agree with the Stokes–Einstein–Debye relation. The dipole relaxation times calculated are discussed in terms of simple and useful approximations, such as the Glarum–Powles and Fatuzzo–Mason models.     

Effect of the R119G mutation on human P5CR structure and its interactions with NAD: Insights derived from molecular dynamics simulation and free energy analysis

Pyrroline-5-carboxylate reductase (P5CR), an enzyme with conserved housekeeping roles, is involved in the etiology of cutis laxa. While previous work has shown that the R119G point mutation in the P5CR protein is involved, the structural mechanism behind the pathology remains to be elucidated. In order to probe the role of the R119G mutation in cutis laxa, we performed molecular dynamics (MD) simulations, essential dynamics (ED) analysis, and Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations on wild type (WT) and mutant P5CR-NAD complex. These MD simulations and ED analyses suggest that the R119G mutation decreases the flexibility of P5CR, specifically in the substrate binding pocket, which could decrease the kinetics of the cofactor entrance and egress. Furthermore, the MM-PBSA calculations suggest the R119G mutant has a lower cofactor binding affinity for NAD than WT. Our study provides insight into the possible role of the R119G mutation during interactions between P5CR and NAD, thus bettering our understanding of how the mutation promotes cutis laxa.     

RDX基PBX的模型、结构、能量及其与感度关系的分子动力学研究

以RDX（环三亚甲基三硝胺）为基、PS（聚苯乙烯）为粘结剂构成PBX（高聚物粘结炸药）的MD（分子动力学）模拟初始模型.比较分别以1根46链节和2根23链节PS置于RDX（001）晶面上的两种（PBX1和PBX2）模型下的MD模拟结果,发现二者的结构、相互作用能和力学性能均很接近.取PBX2进行5种温度（195,245,295,345和395 K）下的NPT系综、MD模拟系统研究,发现随温度依次升高,各体系中RDX引发键N NO2键的最大键长（Lmax）递增,N–N键连的N与N之间的双原子作用能（EN-N）和内聚能密度（CED）递减,与感度随温度升高而增大的实验事实相一致.综合已有工作,对高能复合材料（如PBX和固体推进剂等）的感度理论研究,建议关注其中易爆燃组分在外界刺激下的结构和能量变化,其引发键Lmax和作为引发键强度度量的双原子作用能（如EN-N）,可作为热和撞击感度相对大小的理论判据.     

Studies of the surface layer structure and properties of poly(styrene/α-t-butoxy-ω-polyglycidol) microspheres by carbon nuclear magnetic resonance,X-ray photoelectron spectroscopy,and the adsorption of human serum albumin and γ-globulins

The composition and properties of the surface layers of poly(styrene/α-t-butoxy-ω-polyglycidol) [poly(styrene/VB-polyGL)] microspheres synthesized by the radical copolymerization of styrene and α-t-butoxy-ω-vinylbenzyl-polyglycidol (VB-polyGL) macromonomers [number-average molecular weight (M_n) = 950 or 2700] were investigated with X-ray photoelectron spectroscopy, ¹³C NMR, and the adsorption of human serum albumin and γ-globulins. The number-average diameter of the synthesized microspheres was 220 nm. Their surface layers were rich in polyglycidol, with polyglycidol-to-polystyrene unit ratios of 0.443 (VB-polyGL with M_n = 950) and 0.427 (VB-polyGL with M_n = 2700). In suspensions of poly(styrene/VB-polyGL) particles in D₂O, the polymer chains in the polyglycidol-rich surface layers were highly mobile, allowing the registration of polyglycidol ¹³C NMR spectra with standard procedures for polymer solutions. In these spectra, the signals of the relatively immobile polystyrene segments were absent. The spin–lattice relaxation times (T₁) measured for polyglycidol in the microsphere surface layers and for VB-polyGL macromonomers in solution were very close, indicating similar degrees of motion in bound (in particle surface layers) and free (in solution) polyglycidol macromolecules. Studies of protein adsorption revealed that hydrophilic polyglycidol layers were protein-repellent. It was found that longer polyglycidol chains in particle surface layers were more mobile (higher T₁ values) and provided better protection against protein adsorption. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 615–623, 2004     

Discovery of potential inhibitors targeting the kinase domain of polynucleotide kinase/phosphatase (PNKP): Homology modeling,virtual screening based on multiple conformations,and molecular dynamics simulation

In recent years, the level of interest has been increased in developing the DNA-repair inhibitors, to enhance the cytotoxic effects in the treatment of cancers. Polynucleotide kinase/phosphatase (PNKP) is a critical human DNA repair enzyme that repairs DNA strand breaks by catalyzing the restoration of 5’-phosphate and 3’-hydroxyl termini that are required for subsequent processing by DNA ligases and polymerases. PNKP is the only protein that repairs the 3′-hydroxyl group and 5′-phosphate group, which depicts PNKP as a potential therapeutic target. Besides, PNKP is the only DNA-repair enzyme that contains the 5′-kinase activity, therefore, targeting this kinase domain would motivate the development of novel PNKP-specific inhibitors. However, there are neither crystal structures of human PNKP nor the kinase inhibitors reported so far. Thus, in this present study, a sequential molecular docking-based virtual screening with multiple PNKP conformations integrating homology modeling, molecular dynamics simulation, and binding free energy calculation was developed to discover novel PNKP kinase inhibitors, and the top-scored molecule was finally submitted to molecular dynamics simulation to reveal the binding mechanism between the inhibitor and PNKP. Taken together, the current study could provide some guidance for the molecular docking based-virtual screening of novel PNKP kinase inhibitors.     

QSAR based virtual screening derived identification of a novel hit as a SARS CoV-229E 3CLpro Inhibitor: GA-MLR QSAR modeling supported by molecular Docking,molecular dynamics simulation and MMGBSA calculation approaches

Congruous coronavirus drug targets and analogous lead molecules must be identified as quickly as possible to produce antiviral therapeutics against human coronavirus (HCoV SARS 3CLpro) infections. In the present communication, we bear recognized a HIT candidate for HCoV SARS 3CLpro inhibition. Four Parametric GA-MLR primarily based QSAR model (R2:0.84, R2adj:0.82, Q2loo: 0.78) was once promoted using a dataset over 37 structurally diverse molecules along QSAR based virtual screening (QSAR-VS), molecular docking (MD) then molecular dynamic simulation (MDS) analysis and MMGBSA calculations. The QSAR-based virtual screening was utilized to find novel lead molecules from an in-house database of 100 molecules. The QSAR-vS successfully offered a hit molecule with an improved _PEC₅₀ value from 5.88 to 6.08. The benzene ring, phenyl ring, amide oxygen and nitrogen, and other important pharmacophoric sites are revealed via MD and MDS studies. Ile164, Pro188, Leu190, Thr25, His41, Asn46, Thr47, Ser49, Asn189, Gln191, Thr47, and Asn141 are among the key amino acid residues in the S1 and S2 pocket. A stable complex of a lead molecule with the HCoV SARS 3CLpro was discovered using MDS. MM-GBSA calculations resulted from MD simulation results well supported with the binding energies calculated from the docking results. The results of this study can be exploited to develop a novel antiviral target, such as an HCoV SARS 3CLpro Inhibitor.