Morphology transformation of hybrid micelles self-assembled from rod-coil block copolymer and nanoparticles

Hybrid polymeric micelles self-assembled from a mixture containing poly(γ-benzyl-L-glutamate)-block-poly(ethylene glycol) (PBLG-b-PEG) block copolymer and gold nanoparticles (AuNPs) were prepared. The effect of AuNPs on the self-assembly behavior of PBLG-b-PEG was studied both experimentally by transmission electron microscopy, scanning electron microscopy, and laser light scattering and computationally using dissipative particle dynamics (DPD) simulations. It was found that, the pure PBLG-b-PEG block copolymer self-assembles into long cylindrical micelles. By introducing AuNPs to the stock block copolymer solution, the formed aggregate morphology transforms to spherical micelles. The DPD simulation results well reproduced the morphological transformations observed in the experiments. And the simulation revealed that the main reason for the aggregate morphology transformation is the breakage of ordered packing of PBLG rods in micelle core by the added nanoparticles. Moreover, from the DPD simulations, the distribution information on nanoparticles was obtained. The nanoparticles were found to prefer to locate near the core/shell interface as well as in the core center of the micelles. The combination of experimental and simulation methods lead to a comprehensive understanding of such a complex self-assembly system.     

偏氟乙烯/三氟氯乙烯交替共聚物在TATB表面吸附的分子动力学模拟

采用COMPASS力场和NVT正则系综的动力学模拟方法, 搭建了聚合度分别为10, 50和100的偏氟乙烯(VDF)/三氟氯乙烯(CTFE)交替共聚物, 对交替共聚物在1,3,5-三氨基-2,4,6-三硝基苯(TATB)的(0,0,1)晶面上的吸附和结构进行了分子动力学(MD)模拟. 结果表明, 在300～320 K温区, 聚合度为100的VDF/CTFE交替共聚物链对TATB晶体有理想的表面活性和吸附能力, 以train型构象平铺于TATB表面. 通过对聚合度为10的交替共聚物的多链体系在TATB表面吸附的MD模拟, 表明了VDF/CTFE交替共聚物具有非凝聚吸附的高表面活性特征. 对搭建的乙酸乙酯溶剂化的聚合度为50的VDF/CTFE交替共聚物在TATB晶体表面吸附的模拟, 实验证明了溶剂小分子能够降低共聚物链的吸附能力, 且链以tail型构象吸附于TATB表面.     

Conformation and diffusion behavior of ring polymers in solution: a comparison between molecular dynamics, multiparticle collision dynamics, and lattice Boltzmann simulations

We have studied the effect of chain topology on the structural properties and diffusion of polymers in a dilute solution in a good solvent. Specifically, we have used three different simulation techniques to compare the chain size and diffusion coefficient of linear and ring polymers in solution. The polymer chain is modeled using a bead-spring representation. The solvent is modeled using three different techniques: molecular dynamics (MD) simulations with a particulate solvent in which hydrodynamic interactions are accounted through the intermolecular interactions, multiparticle collision dynamics (MPCD) with a point particle solvent which has stochastic interactions with the polymer, and the lattice Boltzmann method in which the polymer chains are coupled to the lattice fluid through friction. Our results show that the three methods give quantitatively similar results for the effect of chain topology on the conformation and diffusion behavior of the polymer chain in a good solvent. The ratio of diffusivities of ring and linear polymers is observed to be close to that predicted by perturbation calculations based on the Kirkwood hydrodynamic theory.     

Molecular dynamics simulations of helix-forming, amine-functionalized m-poly(phenyleneethynylene)s

We present here the results of all-atom and united-atom molecular dynamics (MD) simulations that were used to examine the folding behavior of an amine-functionalized m-poly(phenyleneethynylene) (m-PPE) oligomer in aqueous environment. The parallelized GROMACS MD simulation code and OPLS force field were used for multiple MD simulations of m-PPE oligomers containing 24 phenyl rings in extended, coiled and helix conformations separately in water to determine the minimum energy conformation of the oligomer in aqueous solvent and what interactions are most important in determining this structure. Simulation results showed that the helix is the preferred minimum energy conformation of a single oligomer in water and that Lennard-Jones interactions are the dominant forces for the stabilization of the helix. In addition, these solvophobic interactions are strong enough to maintain the helix conformation at temperatures up to 523 K.     

Molecular dynamics simulation and thermodynamic modeling of the self-assembly of the triterpenoids asiatic acid and madecassic acid in aqueous solution

The self-assembly behavior of the triterpenoids asiatic acid (AA) and madecassic acid (MA), both widely studied bioactive phytochemicals that are similar in structure to bile salts, were investigated in aqueous solution through atomistic-level molecular dynamics (MD) simulation. AA and MA molecules initially distributed randomly in solution were observed to aggregate into micelles during 75 ns of MD simulation. A "hydrophobic contact criterion" was developed to identify micellar aggregates from the computer simulation results. From the computer simulation data, the aggregation number of AA and MA micelles, the monomer concentration, the principal moments of the micelle radius of gyration tensor, the one-dimensional growth exhibited by AA and MA micelles as the aggregation number increases, the level of internal ordering within AA and MA micelles (quantified using two different orientational order parameters), the local environment of atoms within AA and MA in the micellar environment, and the total, hydrophilic, and hydrophobic solvent accessible surface areas of the AA and MA micelles were each evaluated. The MD simulations conducted provide insights into the self-assembly behavior of structurally complex, nontraditional surfactants in aqueous solution. Motivated by the high computational cost required to obtain an accurate estimate of the critical micelle concentrations (CMCs) of AA and MA from evaluation of the average monomer concentration present in the AA and MA simulation cells, a modified computer simulation/molecular-thermodynamic model (referred to as the MCS-MT model) was formulated to quantify the free-energy change associated with optimal AA and MA micelle formation in order to predict the CMCs of AA and MA. The predicted CMC of AA was found to be 59 microM, compared with the experimentally measured CMC of 17 microM, and the predicted CMC of MA was found to be 96 microM, compared with the experimentally measured CMC of 62 microM. The AA and MA CMCs predicted using the MCS-MT model are much more accurate than the CMCs inferred from the monomer concentrations of AA and MA present in the simulation cells after micelle self-assembly (2390 microM and 11,300 microM, respectively). The theoretical modeling results obtained for AA and MA indicate that, by combining computer simulation inputs with molecular-thermodynamic models of surfactant self-assembly, reasonably accurate estimates of surfactant CMCs can be obtained with a fraction of the computational expense that would be required by using computer simulations alone.     

表面活性剂在溶液中聚集形态的动力学模拟

用耗散颗粒动力学模拟方法(DPD)展示了表面活性剂分子在溶液中的聚集形态，用扩散程度表征了表面活性剂溶液中的自组装情况。结果发现：这种分子动力学模拟方法能够直观地得到表面活性剂的聚集形态；随着表面活性剂的浓度增加，聚集形态依次从球状胶束、棒状或虫状胶束，六角状相，向层状相变化。     

Self-assembly behavior of ABA coil-rod-coil triblock copolymers: a Brownian dynamics simulation approach

The self-assembly behavior of ABA coil-rod-coil triblock copolymers in a selective solvent was studied by a Brownian molecular dynamics simulation method. It was found that the rod midblock plays an important role in the self-assembly of the copolymers. With a decrease in the segregation strength, ?(RR), of rod pairs, the aggregate structure first varies from a smecticlike disk shape to a long twisted string micelle and then to small aggregates. The influence of the block length and the asymmetry of the triblock copolymer on the phase behavior were studied and the corresponding phase diagrams were mapped. It was revealed that the variation of these parameters has a profound effect on microstructure. The simulation results are consistent with experimental results. Compared to rod-coil diblock copolymers, the coil-rod-coil triblock copolymers has a larger entropy penalty associated with the interfacial grafting density of the aggregate, leading to a higher ?(RR) value for structural transitions.     

Interaction of a tripeptide with cesium perfluorooctanoate micelles

The interaction of alanyl-phenylalanyl-alanine (Ala-Phe-Ala) with the micelles formed by cesium perfluorooctanoate (CsPFO) in water was studied in the isotropic phase by means of 1H NMR and by molecular dynamics (MD) simulations. Information on the location of the peptide was experimentally obtained from selective variations in Ala-Phe-Ala chemical shifts and from differential line broadening in the presence of the paramagnetic ion Mn2+. The peptide-micelle association constant was estimated analyzing the chemical shift variations of the most sensitive Ala-Phe-Ala resonances with the peptide concentration. MD simulations of Ala-Phe-Ala in the micellar environment confirmed the experimental observations, identifying the hydrogen bonding interactions of the different peptide moieties with the micelle, yielding a binding constant close to the experimental one. NOESY experiments suggest that the peptide in the micellar environment does not adopt a preferred conformation but is mainly unstructured. Details on the conformational behavior of the peptide in the micellar solution observed through MD were consistent with a different conformational equilibrium in the proximity of the micelle. Information on Ala-Phe-Ala dynamics was obtained from 1H T1 data and compared to MD simulation results on the overall tumbling motion.     

Solvation structure and dynamics for passivated Au nanoparticle in supercritical CO2: a molecular dynamic simulation

All-atomic molecular dynamics simulations have been performed to study the interfacial structural and dynamical properties of passivated gold nanoparticles in supercritical carbon dioxide (scCO(2)). Simulations were conducted for a 55-atom gold nanocore with thiolated perfluoropolyether as the packing ligands. The effect of solvent density and surface coverage on the structural and dynamical properties of the self-assembly monolayer (SAM) has been discussed. The simulation results demonstrate that the interface between nanoparticle and scCO(2) solvent shows a depletion region due to the preclusion of SAM. The presence of scCO(2) solvent around the passivated Au nanoparticle can lead to an enhanced extension of the surface SAM. Under full coverage, the structure and conformation of SAM are insensitive to the density change of scCO(2) fluid. This simulation results clarify the microscopic solvation mechanism of passivated nanoparticles in supercritical fluid medium and is expected to be helpful in understanding the scCO(2)-based nanoparticle dispersion behavior.     

Solvophobic and steric effects of side groups on polymer folding: molecular modeling studies of amine-functionalized m-poly(phenyleneethynylene) foldamers in aqueous solution

The folding behavior of five different amine-functionalized m-poly(phenyleneethynylene) (m-PPE) oligomers containing 24 phenyl rings (12 residues, where a residue includes 2 phenyl rings) in water was examined by using a combination of molecular dynamics (MD) and replica exchange molecular dynamics (REMD) simulation techniques. The REMD method employed the highly parallelized GROMACS MD software and a modified OPLS-AA force field to simulate 44 replicas of each solvated system in parallel, with temperatures ranging from 300 to 577 K. Our results showed that the REMD method was more effective in predicting the helical conformation of the m-PPE in water, from an extended structure, than canonical MD methods in the same simulation time. Furthermore, we observed from canonical MD simulations of the explicitly solvated helical m-PPEs at 300 K that the radius of gyration, average helix inner diameter, and average helix pitch of the helical structure all pass through a minima when the side group is R = OC(2)H(5) as R is changed from R = H through OC(4)H(9).     

Self-assembling cyclic peptides: molecular dynamics studies of dimers in polar and nonpolar solvents

The self-assembly of cyclic D,L-alpha-peptides into hollow nanotubes is a crucial mechanistic step in their application as antibacterial and drug-delivery agents. To understand this process, molecular dynamics (MD) simulations were performed on dimers of cyclic peptides formed from cyclo [(-L-Trp-D-N-MeLeu-)4-]2 and cyclo [(-L-Trp-D-Leu-)4-]2 subunits in nonpolar (nonane) and polar (water) solvent. The dimers were observed to be stable only in nonpolar solvent over the full 10 ns length of the MD trajectory. The behavior of the dimers in different solvents is rationalized in terms of the intersubunit hydrogen bonding, hydrogen bonding with the solvent, and planarity of the rings. It is shown that the phi and psi dihedral angles of a single uncapped ring in nonane lie in the beta-sheet region of the Ramachandran plot, and the ring stays in a flat conformation. Steered MD (SMD) simulations based on Jarzynski's equality were performed to obtain the potential of mean force as a function of the distance between the two rings of the capped dimer in nonane. It is also shown that a single peptide subunit prefers to reside close to the nonane/water interface rather than in bulk solvent because of the amphiphilic character of the peptide ring. The present MD results build the foundation for using MD simulations to study the mechanism of the formation of cyclic peptide nanotubes in lipid bilayers.     

Conformational transition and energy landscape of ErbB4 activated by neuregulin1β: one microsecond molecular dynamics simulations

ErbB4, a receptor tyrosine kinase of the ErbB family, plays crucial roles in cell growth and differentiation, especially in the development of the heart and nervous system. Ligand binding to its extracellular region could modulate the activation process. To understand the mechanism of ErbB4 activation induced by ligand binding, we performed one microsecond molecular dynamics (MD) simulations on the ErbB4 extracellular region (ECR) with and without its endogenous ligand neuregulin1β (NRG1β). The conformational transition of the ECR-ErbB4/NRG1β complex from a tethered inactive conformation to an extended active-like form has been observed, while such large and function-related conformational change has not been seen in the simulation on the ECR-ErbB4, suggesting that ligand binding is indeed the active inducing force for the conformational transition and further dimerization. On the basis of MD simulations and principal component analysis, we constructed a rough energy landscape for the conformational transition of ECR-ErbB4/NRG1β complex, suggesting that the conformational change from the inactive state to active-like state involves a stable conformation. The energy barrier for the tether opening was estimated as ~2.7 kcal/mol, which is very close to the experimental value (1-2 kcal/mol) reported for ErbB1. On the basis of the simulation results, an atomic mechanism for the ligand-induced activation of ErbB4 was postulated. The present MD simulations provide a new insight into the conformational changes underlying the activation of ErbB4.     

Refinement of the NMR structures of alpha-conotoxin MI using molecular dynamics simulation with explicit solvent water and a full molecular force field

Three NMR structures of alpha-conotoxin MI, a potent antagonist of the nicotinic acetylcholine receptor, have been refined using molecular dynamics (MD) simulation with explicit water. Although the convergence of the NMR structures of alpha-conotoxin MI was not sufficient to provide detailed structural features, the average structures obtained from MD simulations converged to one conformation, providing structural characteristics. The resulting structure was also found to be consistent with the results of amide proton-exchange experiments. These results demonstrate that MD simulation with explicit solvent water is very useful in refining NMR structures.     

Influence of an Unnatural Amino Acid Side Chain on the Conformational Dynamics of Peptides

In this work, a non‐natural amino acid, H‐propargylglycine‐OH (Pra), is chosen to examine the side‐chain effect on the backbone conformation of small peptides. The conformations of two synthesized Pra‐containing tripeptides, Ac‐Pra‐Pra‐NH₂ (PPTP) and Ac‐Pra‐Ala‐NH₂ (PATP), are examined by infrared (IR) spectroscopy in combination with molecular dynamics (MD) simulations and quantum chemical computations. By analyzing the joint distributions of backbone torsional angles, several significant conformations can be identified for the two tripeptides solvated in D₂O. At room temperature, 44 % of PPTP exists in the α‐α conformation and 33 % of PATP exists in the α‐polyproline‐II conformation. Larger structural inhomogeneity is seen in both cases by MD simulations at elevated temperatures. Thus even a small side chain, such as the propargyl group can significantly alter the peptide backbone conformations. The results suggest that there is no overwhelming conformational propensity of the Pra residue in short peptides. IR spectra simulated in the amide‐I region using two different methods, reasonably reproduce the experimental IR spectra and their temperature dependence.     

Classical and quantum mechanical/molecular mechanical molecular dynamics simulations of alanine dipeptide in water: comparisons with IR and vibrational circular dichroism spectra

We have implemented the combined quantum mechanical (QM)/molecular mechanical (MM) molecular dynamics (MD) simulations of alanine dipeptide in water along with the polarizable and nonpolarizable classical MD simulations with different models of water. For the QM/MM MD simulation, the alanine dipeptide is treated with the AM1 or PM3 approximations and the fluctuating solute dipole moment is calculated by the Mulliken population analysis. For the classical MD simulations, the solute is treated with the polarizable or nonpolarizable AMBER and polarizable CHARMM force fields and water is treated with the TIP3P, TIP4P, or TIP5P model. It is found that the relative populations of right-handed alpha-helix and extended beta and P(II) conformations in the simulation trajectory strongly depend on the simulation method. For the QM/MM MD simulations, the PM3/MM shows that the P(II) conformation is dominant, whereas the AM1/MM predicts that the dominant conformation is alpha(R). Polarizable CHARMM force field gives almost exclusively P(II) conformation and other force fields predict that both alpha-helical and extended (beta and P(II)) conformations are populated with varying extents. Solvation environment around the dipeptide is investigated by examining the radial distribution functions and numbers and lifetimes of hydrogen bonds. Comparing the simulated IR and vibrational circular dichroism spectra with experimental results, we concluded that the dipeptide adopts the P(II) conformation and PM3/MM, AMBER03 with TIP4P water, and AMBER polarizable force fields are acceptable for structure determination of the dipeptide considered in this paper.     

Microstructure and self-assembly of inhomogeneous rigid rodlike chains between two neutral surfaces: A hybrid density functional approach

We use a hybrid density functional approach to investigate the microstructure and self-assembly of inhomogeneous rigid rodlike chains between two neutral surfaces, i.e., two hard walls. In the calculation, the rodlike molecule is modeled as a rigid rod linearly connected by the tangent sphere beads. The hybrid method combines a single-chain Monte Carlo (MC) simulation for the ideal-gas part of Helmholtz energy and a DFT approach for the excess Helmholtz energy. The DFT approach includes a modified fundamental measure theory for the excluded-volume effect, the first order thermodynamics perturbation theory for chain connectivity, and the mean field approximation for the van der Waals attraction. We investigate the effect of the chain length (i.e., aspect ratio) of the rodlike molecule and the separation between two surfaces on the microstructure and self-assembly of inhomogeneous rigid rodlike chains. For the athermal systems, the rodlike chain fluids present a smaller partitioning coefficient compared to the flexible chain fluids. For the thermal systems, lamellar thin films formed by the rigid rodlike molecules perpendicular to the neutral surface are observed. The effects of the head-head interaction and the separation on the self-assembly of the rodlike chain fluids in the slit are investigated.     

Molecular dynamics simulations of cyclosporin A: The crystal structure and dynamic modelling of a structure in apolar solution based on NMR data

Summary The conformation of the immunosuppressive drug cyclosporin A (CPA), both in apolar solution and in crystalline state, has been studied by computer simulation techniques. Three molecular dynamics (MD) simulations have been performed: one modelling the crystal structure and two modelling the structure in apolar solution, using a restrained MD approach in which data from nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy are taken into account. The simulation of the crystalline state (MDC) concerns a system of 4 unit cells containing 16 cyclosporin A molecules and 22 water molecules, which is simulated using crystalline periodic boundary conditions. The simulations modelling the apolar solvent conformation (MDS) concern one isolated cyclosporin A molecule. In these simulations an extra term in the interatomic potential function is used, which forces the molecule to satisfy a set of 57 atom-atom distance constraints originating from nuclear Overhauser effects (NOEs) obtained from NMR spectroscopy and one distance constraint deduced from IR spectroscopy.From a comparison of the results of the crystal simulation to those of the X-ray experiment in terms of structure, atomic fluctuations, hydrogen bond pattern, etc., it is concluded that the force field that is used yields an adequate representation of crystalline cyclosporin A. Secondly, it is shown that the dynamic modelling technique that is used to obtain a structure in a polar solution from NMR distance information works well. Starting from initial conformations which have a root mean square difference of 0.14 nm both distance restrained MD simulations converge to the same final solution structure. A comparison of the crystal structure of cyclosporin A and the one in apolar solution shows that there are significant differences. The overall difference in atomic positions is 0.09 nm for the C_x atoms and 0.17 nm for all atoms. In apolar solution, the molecule is slightly more bent and the side chains of 1 MeBmt and 10 MeLeu adopt a different conformation.Abbreviations MeBmt (4R)-4[(E)-2-butenyl]-4-methyl-l-Threonine - MD Molecular dynamics - EM Energy minimization - MDC Molecular dynamics simulation of the crystal - MDS1 Restrained molecular dynamics simulation to obtain the structure in solution starting from the crystal structure - MDS2 Like MDS1, but starting from the SMS structure - SMS Proposed structure in solution, obtained by model building - XRAY An X-ray structure - CPA Cyclosporin A - NMR Nuclear magnetic resonance spectroscopy - NOE Nuclear Overhauser enhancement - MDS1 Mean simulated structure obtained by averaging over the time period 20–40 ps of the MDS1 simulation - MDS2 Mean simulated structure obtained by averaging over the time period 10–30 ps of the MDS2 simulation - Mean simulated structure obtained by averaging over the time period 7–15 ps and over the 16 asymmetric units in the computational box of the MDC simulation.     

Coarse-grained molecular dynamics simulations of the sphere to rod transition in surfactant micelles

Surfactant molecules self-assemble in aqueous solutions to form various micellar structures such as spheres, rods, or lamellae. Although phase transitions in surfactant solutions have been studied experimentally, their molecular mechanisms are still not well understood. In this work, we show that molecular dynamics (MD) simulations using the coarse-grained (CG) MARTINI force field and explicit CG solvent, validated against atomistic MD studies, can accurately represent micellar assemblies of cetyltrimethylammonium chloride (CTAC). The effect of salt on micellar structures is studied for aromatic anionic salts, e.g., sodium salicylate, and simple inorganic salts, e.g., sodium chloride. Above a threshold concentration, sodium salicylate induces a sphere to rod transition in the micelle. CG MD simulations are shown to capture the dynamics of this shape transition and support a mechanism based on the reduction in the micelle-water interfacial tension induced by the adsorption of the amphiphilic salicylate ions. At the threshold salt concentration, the interface is nearly saturated with adsorbed salicylate ions. Predictions of the effect of salt on the micelle structure in different CG solvent models, namely, single-site standard water and three-site polarizable water, show qualitative agreement. This suggests that phase transitions in aqueous micelle solutions could be investigated by using standard CG water models which allow for 3 orders of magnitude reduction in the computational time as compared to that required for atomistic MD simulations.     

VDF-CTFE共聚物在TATB表面吸附链构象的分子动力学模拟

采用COMPASS力场和NVT正则系综的动力学计算模拟了偏氟乙烯(PVDF)与三氟氯乙烯(PCTFE)及其共聚物在1,3,5-三氨基-2,4,6-三硝基苯(TATB)表面吸附能和吸附链的构象. 结果表明, 氟聚合物链与TATB表面距离小于0.8 nm时, 产生吸附放热效应. 在TATB表面, PVDF有强吸附作用, 而PCTFE的吸附能力差. 对VDF与CTFE单体摩尔比为1∶1, 1∶2, 1∶3和1∶4的共聚物吸附模拟结果表明, 共聚物的组成和链的序列结构对其在TATB表面的吸附行为和吸附链构象影响很大. 单体摩尔比为1∶2的交替共聚物链的吸附效果最佳. 随着共聚物链段中PCTFE链节的增加, 聚合物链的刚性增大, 在TATB表面吸附能力逐渐下降、吸附能亦降低, 尾型(tail)或环型(loop)构象数逐渐增多.