Varying the degree of oxidation of graphite: effect of oxidation time and oxidant mass.

In this work, we employ a fast and less toxic modified Hummers' method to develop graphene oxide (GO) with varying degrees of oxidation and investigate the effect of the latter on the structure and the thermal properties of the synthesized materials. Two different key parameters, the time of the oxidation reaction and the mass of the oxidation agent, were systematically altered in order to fine tune the oxidation degree. All graphene oxides were characterized by a plethora of experimental techniques, like X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) as well as infrared spectroscopy (IR) and X-ray photoelectron spectroscopy (XPS) for their structural, thermal and chemical identification. The results revealed that for a certain amount of oxidant, the time does not affect the final degree of oxidation of the materials, at least for the examined reaction times, because very similar structural patterns and thermal properties were obtained. At the same time, the oxygen-containing functional groups were found very similar. On the other hand, the degree of oxidation was found highly dependent on the mass of the oxidizing agent. XRD analysis showed a systematic increase of the interlayer distance of the synthesized GOs with the increase of the oxidant mass, whereas both the enthalpy of reduction and the % weight loss were increased. Moreover, XPS measurements provided a quantitative evaluation of the amount of carbon and oxygen in the materials; the increase of the oxidant mass led to a decrease of the total carbon content with the concurrent increase of the total oxygen amount.

Therapeutic stapled peptides: Efficacy and molecular targets.

Peptide stapling, by employing a stable, preformed alpha-helical conformation, results in the production of peptides with improved membrane permeability and enhanced proteolytic stability, compared to the original peptides, and provides an effective solution to accelerate the rapid development of peptide drugs. Various reviews present peptide stapling chemistries, anchoring residues and one- or two-component cyclization, however, therapeutic stapled peptides have not been systematically summarized, especially focusing on various disease-related targets. This review highlights the latest advances in therapeutic peptide drug development facilitated by the application of stapling technology, including different stapling techniques, synthetic accessibility, applicability to biological targets, potential for solving biological problems, as well as the current status of development. Stapled peptides as therapeutic drug candidates have been classified and analysed mainly by receptor- and ligand-based stapled peptide design against various diseases, including cancer, infectious diseases, inflammation, and diabetes. This review is expected to provide a comprehensive reference for the rational design of stapled peptides for different diseases and targets to facilitate the development of therapeutic peptides with enhanced pharmacokinetic and biological properties.

Investigating the complexation propensity of self-assembling dipeptides with the anticancer peptide-drug Bortezomib: a computational study.

The investigation of potential self-assembled peptides as carriers for the delivery of anticancer drug Bortezomib is the topic of the present study. The self-assembly of Bortezomib in water is examined using all-atom molecular dynamics simulations and corresponding experimental results from FESEM experiments. In addition, a series of dipeptides with a similar chemical formula to Bortezomib with hydrogel-forming ability are being investigated for their propensity to bind to the drug molecule. Dipeptides are divided into two classes, the protected FF (Fmoc-FF and Z-FF) and the LF-based (Cyclo-LF and LF) ones. The thermodynamic stability of the complexes formed in an aqueous environment, as well as key morphological features of the nanoassemblies are investigated at the molecular level. Binding enthalpy between Bortezomib and dipeptides follows the increasing order: LF < Cyclo-LF < Fmoc-FF < Z-FF under both van der Waals and electrostatic contributions. Protected FF dipeptides have a higher affinity for the drug molecule, which will favor its entrapment, giving them an edge over the LF based dipeptides. By evaluating the various measures, regarding both the binding between the two components and the eventual ability of controlled drug release, we conclude that the protected FF class is a more suitable candidate for drug release of Bortezomib, whereas among its two members, Fmoc-FF appears to be more promising. The selection of the optimal candidates based on the present computational study will be a stepping stone for future detailed experimental studies involving the encapsulation and controlled release of Bortezomib both in vitro and in vivo.

Structure of amino acid sequence-reversed wtRop protein: insights from atomistic molecular dynamics simulations.

This study aims to the investigation of the advantages of designing new proteins presume upon a 'bias' sequence of amino acids, based on the reversed sequence of parent proteins, such as the retro ones. The structural simplicity of wtRop offers a very attractive model system to study these aspects. The current work is based on all-atom Molecular Dynamics (MD) simulations and corresponding experimental evidence on two different types of reversed wtRop protein, one with a fully reversed sequence of amino acids (rRop) and another with a partially reversed sequence (prRop), where only the five residues of the loop region (30ASP-34GLN) were not reversed. The exploration of the structure of the two retro proteins is performed highlighting the similarities and the differences with their parent protein, by employing various measures. Two models have been studied for both reversed proteins, a dimeric and a monomeric with the former one found to be more stable than the latter. Preferable equilibrium structures that the protein molecule can attain are explored, indicating the equilibration pathway. Simulation findings indicate a disruption of the α-helical structure and the appearance of additional secondary structures for both retro proteins. Reduced structural stability compared to their parent protein (wtRop) is also found. A corruption of the hydrophobic core is observed in the dimeric models. Furthermore, the simulations findings are consistent with the experimental characterization of prRop by circular dichroism spectroscopy (CD) which highlights an unstable, highly α-helical protein.Communicated by Ramaswamy H. Sarma.

Self-Assembly of Phenylalanine-Leucine, Leucine-Phenylalanine, and Cyclo(-leucine-phenylalanine) Dipeptides through Simulations and Experiments.

For over two decades, peptide self-assembly has been the focus of attention and a great source of inspiration for biomedical and nanotechnological applications. The resulting peptide nanostructures and their properties are closely related to the information encoded within each peptide building block, their sequence, and their modes of self-organization. In this work. we assess the behavior and differences between the self-association of the aromatic-aliphatic Phe-Leu dipeptide compared to its retro-sequence Leu-Phe and cyclic Cyclo(-Leu-Phe) counterparts, using a combination of simulation and experimental methods. Detailed all-atom molecular dynamics (MD) simulations offer a quantitative prediction at the molecular level of the conformational, dynamical and structural properties of the peptides' self-assembly, while field emission scanning electron microscopy (FESEM) experiments allow microscopic observation of the self-assembled end-structures. The complementarity and qualitative agreement between the two methods not only highlights the differences between the self-assembly propensity of cyclic and linear retro-sequence peptides but also sheds light on underlying mechanisms of self-organization. The self-assembling propensity was found to follow the order: Cyclo(-Leu-Phe) > Leu-Phe > Phe-Leu.

Dynamics of Polymer Chains in Poly(ethylene oxide)/Silica Nanocomposites via a Combined Computational and Experimental Approach.

The dynamics of polymer chains in poly(ethylene oxide)/silica (PEO/SiO2) nanoparticle nanohybrids have been investigated via a combined computational and experimental approach involving atomistic molecular dynamics simulations and dielectric relaxation spectroscopy (DRS) measurements. The complementarity of the approaches allows us to study systems with different polymer molecular weights, nanoparticle radii, and compositions across a broad range of temperatures. We study the effects of spatial confinement, which is induced by the nanoparticles, and chain adsorption on the polymer's structure and dynamics. The investigation of the static properties of the nanocomposites via detailed atomistic simulations revealed a heterogeneous polymer density layer at the vicinity of the PEO/SiO2 interface that exhibited an intense maximum close to the inorganic surface, whereas the bulk density was reached for distances ∼1-1.2 nm away from the nanoparticle. For small volume fractions of nanoparticles, the polymer dynamics, probed by the atomistic simulations of low-molecular-weight chains at high temperatures, are consistent with the presence of a thin adsorbed layer that exhibits slow dynamics, with the dynamics far away from the nanoparticle being similar to those in the bulk. However, for high volume fractions of nanoparticles (strong confinement), the dynamics of all polymer chains were predicted slower than that in the bulk. On the other hand, similar dynamics were found experimentally for both the local ß-process and the segmental dynamics for high-molecular-weight systems measured at temperatures below the melting temperature of the polymer, which were probed by DRS. These differences can be attributed to various parameters, including systems of different molecular weights and nanoparticle states of dispersion, the different temperature range studied by the different methods, the potential presence of a reduced-mobility PEO/SiO2 interfacial layer that does not contribute to the dielectric spectrum, and the presence of amorphous-crystalline interfaces in the experimental samples that may lead to a different dynamical behaviors of the PEO chains.

Effects of the structure of lipid-based agents in their complexation with a single stranded mRNA fragment: a computational study.

In this work we employed fully atomistic molecular dynamics simulations, aiming towards a better understanding of the mechanisms associated with the formation and the stability of lipid-based RNA nanoassemblies, in an aqueous environment. We examined two groups of lipid-based complexation agents, differing in the degree of hydrophobicity and in the overall charge. The first group was comprised of cationic ionizable agents while the second included electrically neutral amphoteric phosphatidylcholine lipids. It was found that the overall charge of the complexation agents played the most decisive role in the energetics of the lipid/RNA association, while their degree of hydrophobicity affected their self-assembly and their complexation kinetics. The latter also affected the structural stability of the formed complexes since the water entrapped within the clusters of the less hydrophobic agents appeared to reduce the coherence of the lipid-RNA nanoassemblies. The combined effects of the aforementioned attributes dictated also the RNA conformation after complexation. The results from the present study provide thus new insight towards controlling the morphology, the energetic stability and the structural integrity of the formed complexes.

Structure and Thermal Stability of wtRop and RM6 Proteins through All-Atom Molecular Dynamics Simulations and Experiments.

In the current work we study, via molecular simulations and experiments, the folding and stability of proteins from the tertiary motif of 4-α-helical bundles, a recurrent motif consisting of four amphipathic α-helices packed in a parallel or antiparallel fashion. The focus is on the role of the loop region in the structure and the properties of the wild-type Rop (wtRop) and RM6 proteins, exploring the key factors which can affect them, through all-atom molecular dynamics (MD) simulations and supporting by experimental findings. A detailed investigation of structural and conformational properties of wtRop and its RM6 loopless mutation is presented, which display different physical characteristics even in their native states. Then, the thermal stability of both proteins is explored showing RM6 as more thermostable than wtRop through all studied measures. Deviations from native structures are detected mostly in tails and loop regions and most flexible residues are indicated. Decrease of hydrogen bonds with the increase of temperature is observed, as well as reduction of hydrophobic contacts in both proteins. Experimental data from circular dichroism spectroscopy (CD), are also presented, highlighting the effect of temperature on the structural integrity of wtRop and RM6. The central goal of this study is to explore on the atomic level how a protein mutation can cause major changes in its physical properties, like its structural stability.

Self-assembly of diphenylalanine peptides on graphene via detailed atomistic simulations.

The self-assembly of diphenylalanine peptides (FF) on a graphene layer, in aqueous solution, is investigated, through all atom molecular dynamics simulations. Two interfacial systems are studied, with different concentrations of dipeptides and the results are compared with an aqueous solution of FF at room temperature. Corresponding length and time scales of the formed structures are quantified providing important insight into the adsorption mechanism of FF onto the graphene surface. A hierarchical formation of FF structures is observed involving two sequential processes: first, a stabilized interfacial layer of dipeptides onto the graphene surface is formulated, which next is followed by the development of a structure of self-aggregated dipeptides on top of this layer. The whole procedure is completed in almost 200 ns, whereas self-assembly in the system without graphene is accomplished much faster; in less than 50 ns cylindrical structures, the microscopic signal of the macroscopic fibrillar ones, are formed. Strong π-π* interactions between FF and the graphene lead to a parallel orientation to the graphene layer of the phenyl rings within a characteristic time of 80 ns, similar to the one indicated by the time evolution of the number of adsorbed FF atoms at the surface. Reduction in the number of hydrogen bonds between FF peptides is observed because of the graphene layer, since it disturbs their self-assembly propensity. The self-assembly of dipeptides and their adsorption onto the graphene surface destruct the hydrogen bond network of water, in the vicinity of FF, however, the total number of hydrogen bonds in all systems increases, promoting the formed structures.

Complexation of single stranded RNA with an ionizable lipid: an all-atom molecular dynamics simulation study.

Complexation of a lipid-based ionizable cationic molecule (referred to as DML: see main text) with RNA in an aqueous medium was examined in detail by means of fully atomistic molecular dynamics simulations. The different stages of the DML-RNA association process were explored, while the structural characteristics of the final complex were described. The self-assembly process of the DML molecules was examined in the absence and in the presence of nucleotide sequences of different lengths. The formed DML clusters were described in detail in terms of their size and composition and were found to share common features in all the examined systems. Different timescales related to their self-assembly and their association with RNA were identified. It was found that beyond a time period of a few tens of ns, a conformationally stable DML-RNA complex was formed, characterized by DML clusters covering the entire contour of RNA. In a system with a 642-nucleotide sequence, the average size of the complex in the longest dimension was found to be close to 40 nm. The DML clusters were characterized by a rather low surface charge, while a propensity for the formation of larger size clusters close to RNA was noted. Apart from hydrophobic and electrostatic interactions, hydrogen bonding was found to play a key-role in the DML-DML and in the DML-RNA association. The information obtained regarding the structural features of the final complex, the timescales and the driving forces associated with the complexation and the self-assembly processes provide new insight towards a rational design of optimized lipid-based ionizable cationic gene delivery vectors.

Self-assembly of Alanine-Isoleucine and Isoleucine-Isoleucine Dipeptides through Atomistic Simulations and Experiments.

A detailed investigation of the structural and conformational properties of alanine-isoleucine (Ala-Ile) and isoleucine-isoleucine (Ile-Ile) dipeptides is presented in water and in methanol solvents. We propose a consistent combination of complementary simulation and experimental methods, covering a broad range of length and time scales, from the very short (i.e., atomic level), via all-atom molecular dynamics (MD) simulations, up to the macroscopic one, via scanning electron microscopy (SEM) experiments. The examined samples from both simulations and experiment cover a board range of concentrations since these are usually in different concentration windows (i.e., high values in simulations vs low values in experiments). In the present study, there is an overlapping concentration regime and a qualitative agreement between simulation and experimental results is observed. The effect of temperature on the formed structures is found to be small, from both simulation and experiments, when temperature varies from 278 to 300 K. Furthermore, the differences of Ala-Ile and Ile-Ile dipeptides from dialanine (Ala-Ala) and diphenylalanine (Phe-Phe) dipeptides in similar conditions are highlighted. Based on various measures, the strength of the self-assembly propensity of the four dipeptides in aqueous solutions attains the following order: Phe-Phe > Ala-Ile > Ala-Ala > Ile-Ile.

Investigation of the properties of nanographene in polymer nanocomposites through molecular simulations: dynamics and anisotropic Brownian motion.

The dynamical behavior of nanographene sheets dispersed in polymer matrices is investigated through united-atom molecular dynamics simulations. The Brownian motion of the sheet and the anisotropy in its translational and orientational diffusion are the topics of the current study. Different polymer matrices and pristine and functionalized graphene constitute various nanocomposite systems. Interactions between the nanographene flake and the matrix determine the dynamics of the systems. The dynamics is reduced in polyethylene oxide compared to polyethylene matrix, whereas carboxylated sheets move considerably slower than the pristine nanographene in any matrix. Diffusion is anisotropic for short times, while it becomes isotropic in the long time limit. The in-plane motion of the nanographene sheet is faster than the out-of-plane component, in agreement with the diffusion of perfectly oblate ellipsoids. In functionalized graphene, the anisotropy is suppressed. By exploring the temperature effect on both the nanographene sheet and polymer close to the surface, indications for coupling in the motion of the two components are revealed. The strong effect of edge functional groups on the dynamics can be used as a way to control the Brownian motion of nanographene sheets in polymer nanocomposites and consequently tailor the properties of the materials.

Effect of macromolecular architecture on the self-assembly behavior of copolymers in a selective polymer host.

We present a detailed simulation study of the structural and dynamical behavior of star-shaped mikto-arm (polystyrene)8(poly(ethylene oxide))8, (PS)8(PEO)8, copolymers with eight arms of each type, versus that of a linear polystyrene-block-poly(ethylene oxide), PS-b-PEO, diblock, in a selective homopolymer host. Both copolymers are blended at the same weight fraction 33% with an oligomeric PEO host. We use atomistic molecular dynamics simulations to account for the molecular interactions present in the blends and to study quantitatively the dynamical and structural properties of these systems. The presence of the selective oligomeric PEO host leads to the formation of complex self-assembled structures. While cylindrical structures are formed in the case of linear diblock copolymers, mikto-arm star copolymers form percolated interconnected assemblies within the PEO host. The cylindrical objects formed by the linear diblock copolymers exhibit a higher degree of compactness and a weaker temperature dependence than the percolated network formed by their star-shaped analogues. The dynamics is governed primarily by the local structural heterogeneity, i.e., the environment around a segment, which is determined by the interaction between the different components, the macromolecular architecture of the copolymer as well as the associated geometrical constrains. Our data further stress the fact that the structural and dynamical properties in these blends may be controlled/tuned by the macromolecular architecture of the copolymer and/or by adjusting the temperature.

Dynamics and Structure of Monolayer Polymer Crystallites on Graphene.

Graphene-based nanostructured systems and van der Waals heterostructures comprise a material class of growing technological and scientific importance. Joining materials with vastly different properties, polymer/graphene heterosystems promise diverse applications in surface and nanotechnology, including photovoltaics or nanotribology. Fundamentally, molecular adsorbates are prototypical systems to study confinement-induced phase transitions exhibiting intricate dynamics, which require a comprehensive understanding of the dynamical and static properties on molecular time and length scales. Here, we investigate the dynamics and the structure of a single polyethylene chain on free-standing graphene by means of molecular dynamics simulations. In equilibrium, the adsorbed polymer is orientationally linked to the graphene as two-dimensional folded-chain crystallite or at elevated temperatures as a floating solid. The associated superstructure can be reversibly melted on a picosecond time scale upon quasi-instantaneous substrate heating, involving ultrafast heterogeneous melting via a transient floating phase. Our findings elucidate time-resolved molecular-scale ordering and disordering phenomena in individual polymers interacting with solids, yielding complementary information to collective friction and viscosity, and linking to recent experimental observables from ultrafast electron diffraction. We anticipate that the approach will help in resolving nonequilibrium phenomena of hybrid polymeric systems over a broad range of time and length scales.

Collapse transitions in thermosensitive multi-block copolymers: a Monte Carlo study.

Monte Carlo simulations are performed on a simple cubic lattice to investigate the behavior of a single linear multiblock copolymer chain of various lengths N. The chain of type (AnBn)m consists of alternating A and B blocks, where A are solvophilic and B are solvophobic and N = 2nm. The conformations are classified in five cases of globule formation by the solvophobic blocks of the chain. The dependence of globule characteristics on the molecular weight and on the number of blocks, which participate in their formation, is examined. The focus is on relative high molecular weight blocks (i.e., N in the range of 500-5000 units) and very differing energetic conditions for the two blocks (very good-almost athermal solvent for A and bad solvent for B). A rich phase behavior is observed as a result of the alternating architecture of the multiblock copolymer chain. We trust that thermodynamic equilibrium has been reached for chains of N up to 2000 units; however, for longer chains kinetic entrapments are observed. The comparison among equivalent globules consisting of different number of B-blocks shows that the more the solvophobic blocks constituting the globule the bigger its radius of gyration and the looser its structure. Comparisons between globules formed by the solvophobic blocks of the multiblock copolymer chain and their homopolymer analogs highlight the important role of the solvophilic A-blocks.

Dynamics of various polymer-graphene interfacial systems through atomistic molecular dynamics simulations.

The current work refers to a simulation study on hybrid polymer-graphene interfacial systems. We explore the effect of graphene on the mobility of polymers, by studying three well known and widely used polymers, polyethylene (PE), polystyrene (PS) and poly(methyl-methacrylate) (PMMA). Qualitative and quantitative differences in the dynamical properties of the polymer chains in particular at the polymer-graphene interface are detected. Results concerning both the segmental and the terminal dynamics render PE much faster than the other two polymers; PS follows, while PMMA is the slowest one. Clear spatial dynamic heterogeneity has been observed for all model systems, with different dynamical behavior of the adsorbed polymer segments. The segmental relaxation time of the polymer (τseg) as a function of the distance from graphene shows an abrupt decrease beyond the first adsorption layer for PE, as a result of its well-ordered layered structure close to graphene, though a more gradual decay is observed for PS and PMMA. The distribution of the relaxation times of adsorbed segments was also found to be broader than those of the bulk ones for all three polymer-graphene systems.

Effect of solvent on the self-assembly of dialanine and diphenylalanine peptides.

Diphenylalanine (FF) is a very common peptide with many potential applications, both biological and technological, due to a large number of different nanostructures which it attains. The current work concerns a detailed study of the self-assembled structures of FF in two different solvents, an aqueous (H2O) and an organic (CH3OH) through simulations and experiments. Detailed atomistic molecular dynamics (MD) simulations of FF in both solvents have been performed, using an explicit solvent model. The self-assembling propensity of FF in water is obvious while in methanol a very weak self-assembling propensity is observed. We studied and compared structural properties of FF in the two different solvents and a comparison with a system of dialanine (AA) in the corresponding solvents was also performed. In addition, temperature-dependence studies were carried out. Finally, the simulation predictions were compared to new experimental data, which were produced in the framework of the present work. A very good qualitative agreement between simulation and experimental observations was found.

Temperature-induced crystallization in concentrated suspensions of multiarm star polymers: a molecular dynamics study.

In this work, we study temperature-induced crystallization in dense suspensions of multiarm star polymers. This is a continuation of a previous study, which identified and studied the emergence of "glassy" amorphous states, in accordance with experimental observations. We performed molecular dynamics simulations on two types of star polymers: 128-arm stars and 64-arm stars dissolved in n-decane in the temperature range of 20-60 degrees C. These supramolecules are modeled as "soft spheres" interacting via a theoretically developed potential of mean field. Both systems attain a crystalline structure with the characteristics of a face-centered-cubic (fcc) crystal beyond a certain temperature. Kinetics is sensitive on initial configuration. Interestingly, kinetic trapping in "temporary" energy wells leads to highly crystalline structures, yet less ordered than their genuine equilibrium fcc structure. This complication illustrates the difficulty in reaching the equilibrium state, which is crystalline at high temperatures. A structural analysis of the final conformations is presented. The effect of size dispersity and star functionality of soft spheres on microstructure is also examined. Both factors influence crystallization and their effect is quantified by our study.