Nonpolar Side Chains Research Articles

Unusual dielectric response of 4-methyl-1,3-dioxolane derivatives

In this paper, we applied broadband dielectric spectroscopy (BDS) to investigate the molecular dynamics of three 4-methyl-1,3-dioxolane derivatives (MD) whose chemical structures differ in the length of non-polar alkyl side chains. We notice that small changes within their chemical structures have a pronounced impact on parameters characterizing the supercooled dynamics of the compounds selected for this study. Our detailed analysis of the dielectric response reveals that in the supercooled-liquid state besides the structural α-relaxation a sub-α Debye-like relaxation can be clearly distinguished. The observed two relaxation regimes mirror the structural complexity of the investigated MD derivatives. The amphiphilic nature of the investigated compounds and possible interactions between non-polar side chains can rationalize the observed behavior. To follow the molecular arrangement of MD derivatives at low temperatures, we also carried out Raman measurements. Additionally, we performed BDS measurements at elevated pressures which revealed that, as a result of compression, the sub-α contribution to the dielectric response disappeared. The paper concludes with a discussion of open questions about the possible molecular origin of the observed sub-α Debye-like process. These results provide fresh insight into the puzzling nature of the slow supramolecular relaxation modes in low-molecular glass forming liquids.

The liquid structure of elastin.

The protein elastin imparts extensibility, elastic recoil, and resilience to tissues including arterial walls, skin, lung alveoli, and the uterus. Elastin and elastin-like peptides are hydrophobic, disordered, and undergo liquid-liquid phase separation upon self-assembly. Despite extensive study, the structure of elastin remains controversial. We use molecular dynamics simulations on a massive scale to elucidate the structural ensemble of aggregated elastin-like peptides. Consistent with the entropic nature of elastic recoil, the aggregated state is stabilized by the hydrophobic effect. However, self-assembly does not entail formation of a hydrophobic core. The polypeptide backbone forms transient, sparse hydrogen-bonded turns and remains significantly hydrated even as self-assembly triples the extent of non-polar side chain contacts. Individual chains in the assembly approach a maximally-disordered, melt-like state which may be called the liquid state of proteins. These findings resolve long-standing controversies regarding elastin structure and function and afford insight into the phase separation of disordered proteins.

Microporous metal organic framework-based copolymers with efficient gas adsorption capability and high temporal stability

We report new microporous metal-organic 3D coordinated copolymers that exhibit both highly efficient gas adsorption capability and high temporal stability. The Zn-coordinated copolymers (MBCn) were prepared by mixing two organic ligands at various molar ratios: the widely used benzenedicarboxylate (BDC) and its analogous Cn-acid with non-polar alkoxy side chains of various lengths. All MBCn copolymers bearing alkoxy side chains exhibited identical framework structures to that of MOF-5 prepared with only the BDC ligand. Interestingly, compared to MOF-5, MBCn copolymers exhibited up to three times higher gas adsorption properties and higher temporal structural stability. Therefore, copolymerization with organic ligands bearing alkoxy side chains is a promising strategy for the development of new microporous metal-organic hybrid materials. Open image in new window

Probing the interactions between DNA nucleotides and biocompatible liquids: COSMO-RS and molecular simulation study

Abstract Ionic liquid (ILs) have been attracting significant attention as an alternative solvent for DNA extraction/purification and stabilization/storage. In this work, we investigated the interaction between DNA nucleotides and bio-base ILs to get insight into the effect of structural variations of the ILs on the ILs-DNA complex formations. COSMO-RS based quantum calculations and molecular simulation were used to investigate the interaction between the bio-base ILs and DNA nucleotides. Deoxyadenosine 5′ monophosphate (A), Deoxythymidyine 5′ monophosphate (T), Deoxycytidine 5′ monophosphate (C), Deoxyguanosine 5′ monophosphate (G) and their dimers were used to model DNA. 260 ILs (13 cations and 20 amino acid based anions) were evaluated. Activity coefficients at infinite dilution of the DNA nucleotides and excess enthalpy of mixing of the systems were predicted using COSMO-RS model. Solvation free energies of the DNA nucleotides were estimated employing molecular dynamics simulations. The activity coefficients of DNA nucleotides decrease with increasing nucleotides chain length. This implies solubility of the nucleotides is higher for longer DNA nucleotide chain. Piperidinium and pyrrolidinium based ILs show lower activity coefficient than choline and morpholinium based ILs. ILs with anions containing nonpolar side chain amino acids show lower activity coefficient compared to those with polar side chains. This implies strong interaction between the nucleotides and ILs with anions containing nonpolar side chain amino acids compared to anions with polar side chains. Moreover, ILs based on anions with nonpolar side chain show higher negative excess enthalpy of mixing compared to those with polar side chain. Further, solvation free energies of DNA nucleotides in the ILs are negative. Solvation free energy is more negative for dimers compared to monomer nucleotides. ILs based on anions with nonpolar side chain show more negative solvation free energies compared to those with polar side chains.

Conformational landscape of isolated capped amino acids: on the nature of non-covalent interactions

The intramolecular interactions for isolated capped amino acids were investigated computationally by characterizing the conformers for selected amino acids with charged (arginine), polar (asparagine and glutamine), non-polar (alanine, valine and isoleucine), and aromatic (phenylalanine, tryptophan and tyrosine) side chains. The computational method applied combined a molecular mechanics conformational search (with an MMFFs forced field) followed by structural and vibrational density-functional calculations (M06-2X with a triple-ζ Pople’s basis set). The intramolecular forces in each amino acid were analyzed with the Non-Covalent Interactions (NCI) analysis. The results for the 15 most stable conformers studied showed that the structure of isolated capped amino acids resembles those found in proteins. In particular, the two most stable conformers of the nine amino acids investigated exhibit γ L and β L conformations with 7- and 5-membered rings, respectively, as a result of the balance between non-covalent interactions (hydrogen bonds and van der Waals).

Influence of the nature of amino acids on the formation of mesoporous LTA-type zeolite

Hydrothermal crystallization of LTA zeolite has been conducted in the presence of amino acid in order to introduce mesoporosity. Eight different types of proteinogenic amino acids have been employed. The influence of their structure and physicochemical properties on the formation of hierarchically mesoporous LTA (MLTA) zeolite have been investigated. All eight amino acids bearing either basic, or acidic, or polar non-ionizable, or non-polar non-ionizable side chains were able to generate mesopores within LTA crystals. The isoelectric points of amino acids influenced the resulting MLTA's morphology, crystallization kinetics, and impurity content. Pure phase MLTA with controllable shape was obtained. Amino acid with a higher isoelectric point generated smaller and more spherical MLTA in less crystallization time, but induced slightly more impurity FAU phase. The mesopore size generally decreased with hydropathy index so that amino acids with non-polar, non-ionizable side groups generated 14–15 nm mesopores, 5–10 nm smaller than those generated by amino acids in other categories. The hydrophobic moieties in amino acids tended to shrink the mesopores, in contrast with their pore expansion effect in surfactant-mediated mesopore generation route, suggesting a different mesopore formation mechanism. Stability of amino acid during the hydrothermal zeolite synthesis and easy amino acid removal by washing with water was further confirmed. The findings discovered in this study paves a new way for tailoring hierarchical zeolite materials with controlled texture properties.

Charge Separation Mechanisms in Ordered Films of Self-Assembled Donor-Acceptor Dyad Ribbons.

Orthogonal attachment of polar and nonpolar side-chains to a zinc porphyrin-perylenediimide dyad (ZnP-PDI, 1a) is shown to result in self-assembly of ordered supramolecular ribbons in which the ZnP and PDI molecules form segregated π-stacked columns. Following photoexcitation of the ordered ribbons, ZnP+•-PDI-• radical ion pairs form in <200 fs and subsequently produce a 30 ± 3% yield of free charge carriers that live for about 100 μs. Elongating the side chains on ZnP and PDI in 1b enhances the order of the films, but does not result in an increase in free charge carrier yield. In addition, this yield is independent of temperature, free energy of reaction, and the ZnP-PDI distance in the covalent dyad. These results suggest that the free charge carrier yield in this system is not limited by a bound charge transfer (CT) state or promoted by a vibronically hot CT state. Instead, it is likely that π-stacking of the segregated donors and acceptors within the ribbons results in delocalization of the charges following photoexcitation, allowing them to overcome Coulombic attraction and generate free charge carriers.

Low-cost and multi-gram scale synthesis of chiral Nβ-Boc protected α-Nα-hydrazino diesters

An efficient and general low-cost method is described to obtain chiral Nβ-Boc protected α-Nα-hydrazino diester building-blocks (orthogonally and non-orthogonally protected diesters) on multi-gram scale (30mmol) using two successive SN2 reactions. This method is also convenient for the introduction of both polar and nonpolar side chains on the Nα-atom and represents an inexpensive and attractive alternative compared to the more expensive method using commercial oxaziridine reagents for N-amination of α-amino acids.

A driving force for polypeptide and protein collapse.

Experimental measurements and computational results have shown that polypeptide chains, made up of 15-25 glycine residues, collapse to compact structures in water at room temperature. This contrasts with the classic idea that the burial of nonpolar side chains, i.e., the hydrophobic effect, is the driving force of collapse and folding of polypeptides and proteins. It is thus necessary to find a different driving force for polyglycine collapse. The present study aims at showing that the hydrophobic effect has to be re-defined in terms of decrease in solvent-excluded volume associated with chain collapse so that it is characterized by a gain in translational entropy of water molecules. This indicates that the presence of nonpolar side chains is not so important for polypeptide and protein collapse, even though it may be fundamental for the attainment of a unique folded structure.

Molecular basis of the osmolyte effect on protein stability: a lesson from the mechanical unfolding of lysozyme.

Osmolytes are a class of small organic molecules that shift the protein folding equilibrium. For this reason, they are accumulated by organisms under environmental stress and find applications in biotechnology where proteins need to be stabilized or dissolved. However, despite years of research, debate continues over the exact mechanisms underpinning the stabilizing and denaturing effect of osmolytes. Here, we simulated the mechanical denaturation of lysozyme in different solvent conditions to study the molecular mechanism by which two biologically relevant osmolytes, denaturing (urea) and stabilizing (betaine), affect the folding equilibrium. We found that urea interacts favorably with all types of residues via both hydrogen bonds and dispersion forces, and therefore accumulates in a diffuse solvation shell around the protein. This not only provides an enthalpic stabilization of the unfolded state, but also weakens the hydrophobic effect, as hydrophobic forces promote the association of urea with nonpolar residues, facilitating the unfolding. In contrast, we observed that betaine is excluded from the protein backbone and nonpolar side chains, but is accumulated near the basic residues, yielding a nonuniform distribution of betaine molecules at the protein surface. Spatially resolved solvent-protein interaction energies further suggested that betaine behaves in a ligand- rather than solvent-like manner and its exclusion from the protein surface arises mostly from the scarcity of favorable binding sites. Finally, we found that, in the presence of betaine, the reduced ability of water molecules to solvate the protein results in an additional enthalpic contribution to the betaine-induced stabilization.

Tuning the backbones and side chains of cationic meta-linked poly(phenylene ethynylene)s: Different conformational modes, tunable light emission, and helical wrapping of multi-walled carbon nanotubes

We have an ongoing interest in the design and control of helical conformation of water-soluble meta-linked poly(phenylene ethynylene)s (PPEs) and the further development of novel functional materials. Four cationic meta-linked PPEs (P1′-P4′) were synthesized to study the influence of differences in the backbone and side chain structure on their conformations. For P1′ and P4′ without side chains on the para-phenylene units, fluorescence spectroscopic investigations indicated obvious intramolecular helical folding, whereas for P2′ and P3′ with nonpolar and polar side chains on the para-phenylene units respectively, a significantly different conformational mode, namely, cofacial intermolecular aggregation was suggested. The side chains on the para-phenylene units of P2′ and P3′ may be located in the interior cavity of helix and induce steric effect on the formation of helix. However, the introduction of 2,1,3-benzothiadiazole (BT), a low energy gap unit, into the backbone of P4′ showed little influence on the formation of helix despite its larger and more rigid structure than the phenylene unit. Thus, the light emission of these polymers can be tuned in the range from blue, green to yellow with the changes of conformational modes. Moreover, the functionalization of multi-walled carbon nanotubes (MWCNTs) by P4′ in methanol and water, and by using its neutral precursory polymer P4 in tetrahydrofuran was explored through transmission electron microscopy and fluorescence spectroscopy. P4′ was directly observed to individualize MWCNT by forming a monolayer helical wrapping on the nanotube surface, which may be attributed to the backbone flexibility of meta-linked PPE and the strong π−π interactions between the PPE backbone and the CNT surface. Moreover, P4′ served as a better dispersing agent for MWCNT than P4, suggesting that the cationic side groups may act as solubilizing groups which also separated the individual nanotubes because of charge repulsion.

Direct, visible light-sensitized benzylic C[sbnd]H fluorination of peptides using dibenzosuberenone: selectivity for phenylalanine-like residues

A visible light-sensitized benzylic sp3 CH fluorination protocol using dibenzosuberenone (5 mol %) and Selectfluor® is optimized for the direct functionalization of phenylalanine-like residues in short chain peptides. Amino acids, dipeptides, and tripeptides undergo benzylic fluorination with remarkable regioselectivity in the presence of protected basic, acidic, and nonpolar side chains (including those with tertiary sites). Additionally, protecting group compatibility, a gram scale application, and competition experiments were explored.

Improved Morphology and Efficiency of Polymer Solar Cells by Processing Donor–Acceptor Copolymer Additives

A novel wide‐bandgap conjugated polymer PBTA‐FPh based on benzodithiophene‐alt‐benzo[1,2,3]triazole as the main chain and a polar pentafluorothiophenyl (FPh) group in the side chain has been designed and synthesized. In comparison to the pristine polymer PBTA‐BO that consists of nonpolar alkyl side chains, the resulting PBTA‐FPh exhibits less pronounced aggregation while possessing analogous optical and electrochemical bandgaps. Contact angle measurements demonstrate that the surface energy can be enhanced by incorporating FPh moiety, leading to a better miscibility of PBTA‐BO with PC71BM in the presence of a certain amount of PBTA‐FPh. The photoactive layer of PBTA‐BO:PC71BM:PBTA‐FPh with weight ratio of 1:1.2:0.02% exhibits a percolated network with the fibrous features, as revealed by transmission electron microscopy measurements. Of particular interest is the significantly improved photovoltaic performances of polymer solar cell devices for which the power conversion efficiency is enhanced from 6.46% for the control device to 7.91% for device processed with PBTA‐FPh as the polymeric additive. These observations indicate that introducing donor–acceptor type of polymeric additive comprising of polar groups in the side chain can be a promising strategy for the fabrication of high‐performance polymer solar cells.

Impact of Deuteration on the Assembly Kinetics of Transthyretin Monitored by Native Mass Spectrometry and Implications for Amyloidoses.

It is well established that the formation of transthyretin (TTR) amyloid fibrils is linked to the destabilization and dissociation of its tetrameric structure into insoluble aggregates. Isotope labeling is used for the study of TTR by NMR, neutron diffraction, and mass spectrometry (MS). Here MS, thioflavin T fluorescence, and crystallographic data demonstrate that while the X‐ray structures of unlabeled and deuterium‐labeled TTR are essentially identical, subunit exchange kinetics and amyloid formation are accelerated for the deuterated protein. However, a slower subunit exchange is noted in deuterated solvent, reflecting the poorer solubility of non‐polar protein side chains in such an environment. These observations are important for the interpretation of kinetic studies involving deuteration. The destabilizing effects of TTR deuteration are rather similar in character to those observed for aggressive mutations of TTR such as L55P (associated with familial amyloid polyneuropathy).

High-Performance Electron Injection Layers with a Wide Processing Window from an Amidoamine-Functionalized Polyfluorene.

In this work, we present organic light-emitting diodes (OLEDs) utilizing a novel amidoamine-functionalized polyfluorene (PFCON-C) as an electron injection layer (EIL). PFCON-C consists of a polyfluorene backbone to which multiple tertiary amine side chains are connected via an amide group. The influence of molecular characteristics on electronic performance and morphological properties was tested and compared to that of the widely used, literature known amino-functionalized polyfluorene (PFN) and polyethylenimine (PEI). PFCON-C reduces the turn-on voltage (VON) of poly(p-phenylene vinylene) (PPV)-based OLEDs from ∼5 to ∼3 V and increases the maximum power efficiency from <2 to >5 lm W(-1) compared to that of PFN. As a result of its semiconducting backbone, PFCON-C is significantly less sensitive to the processing parameters than PEI, and comparable power efficiencies are achieved for devices where thicknesses of PFCON-C are between 15 and 35 nm. Atomic force microscopy (AFM) measurements indicate that the presence of nonpolar side chains in the EIL material is important for its film-forming behavior, while Kelvin probe measurements suggest that the amount of amine groups in the side chains influences the work-function shift induced by the EIL material. These results are used to suggest strategies for the design of polymeric electron injection layers.

Synthesis and self-assembly of fluorene-vinylene alternating copolymers in “Hairy-Rod” architecture: side chain – mediated tuning of conformation, microstructure and photophysical properties

In the present work, we demonstrate that the side chain choice, as a tunable parameter, is an effective strategy to drive molecular ordering, packing motifs and overall microstructure of a conjugated polymer. By applying Wittig polycondensation novel ‘rod-coil’ structures, in ‘hairy-rod’ architecture, based on fluorenylene vinylene copolymers with well-defined oligomeric side chains were synthesized using ‘T’-shaped or ‘Cross’-shaped p-terphenyl macromonomers. The overall character of the copolymers was systematically varied by attaching of hydrophilic PEG 2000, hydrophobic polar oligo-ε-caprolactone or hydrophobic and non-polar oligostyrene side chains. Self-assembling of the copolymers by simple direct dissolution method was achieved in various solvents by modifying their selectivity in relation to the side chain or main chain. The morphology investigations demonstrated that unique nanofeatures obtained in each case (helical foldamers, vesicles, disks, or helical turns) depend on the nature, number, and position of the side chains which influence the photophysical properties. The ‘hairy-rod’ topology is also responsible for the self-assembly of the materials in molten state, as thermal analysis revealed, and the propensity of the new synthesized conjugated main chain for helical folding was evidenced, as well.

Arginine side chain interactions and the role of arginine as a gating charge carrier in voltage sensitive ion channels.

Gating charges in voltage-sensing domains (VSD) of voltage-sensitive ion channels and enzymes are carried on arginine side chains rather than lysine. This arginine preference may result from the unique hydration properties of the side chain guanidinium group which facilitates its movement through a hydrophobic plug that seals the center of the VSD, as suggested by molecular dynamics simulations. To test for side chain interactions implicit in this model we inspected interactions of the side chains of arginine and lysine with each of the 19 non-glycine amino acids in proteins in the protein data bank. The arginine guanidinium interacts with non-polar aromatic and aliphatic side chains above and below the guanidinium plane while hydrogen bonding with polar side chains is restricted to in-plane positions. In contrast, non-polar side chains interact largely with the aliphatic part of the lysine side chain. The hydration properties of arginine and lysine are strongly reflected in their respective interactions with non-polar and polar side chains as observed in protein structures and in molecular dynamics simulations, and likely underlie the preference for arginine as a mobile charge carrier in VSD.

Structure and Interactions of a Dimeric Variant of sHIP, a Novel Virulence Determinant of Streptococcus pyogenes.

Streptococcus pyogenes is one of the most significant bacterial pathogens in the human population mostly causing superficial and uncomplicated infections (pharyngitis and impetigo) but also invasive and life-threatening disease. We have previously identified a virulence determinant, protein sHIP, which is secreted at higher levels by an invasive compared to a non-invasive strain of S. pyogenes. The present work presents a further characterization of the structural and functional properties of this bacterial protein. Biophysical and structural studies have shown that protein sHIP forms stable tetramers both in the crystal and in solution. The tetramers are composed of four helix-loop-helix motifs with the loop regions connecting the helices displaying a high degree of flexibility. Owing to interactions at the tetramer interface, the observed tetramer can be described as a dimer of dimers. We identified three residues at the tetramer interface (Leu84, Leu88, Tyr95), which due to largely non-polar side-chains, could be important determinants for protein oligomerization. Based on these observations, we produced a sHIP variant in which these residues were mutated to alanines. Biophysical experiments clearly indicated that the sHIP mutant appear only as dimers in solution confirming the importance of the interfacial residues for protein oligomerisation. Furthermore, we could show that the sHIP mutant interacts with intact histidine-rich glycoprotein (HRG) and the histidine-rich repeats in HRG, and inhibits their antibacterial activity to the same or even higher extent as compared to the wild type protein sHIP. We determined the crystal structure of the sHIP mutant, which, as a result of the high quality of the data, allowed us to improve the existing structural model of the protein. Finally, by employing NMR spectroscopy in solution, we generated a model for the complex between the sHIP mutant and an HRG-derived heparin-binding peptide, providing further molecular details into the interactions involving protein sHIP.

Atomic Mechanisms of Stabilizing and Destabilizing Co-Solvents on Protein Stability

Urea and trimethylamine n-oxide (TMAO) are small molecules known to destabilize and stabilize, respectively, the structure of proteins when added to aqueous solution. To unravel the molecular mechanisms of these cosolvents on protein structure we perform explicit all-atom molecular dynamics simulations of extended poly-alanine and poly-leucine dimers. We use an umbrella sampling protocol to compute the potential of mean force (PMF) of dimers at different concentrations of urea and TMAO. We find that the large non-polar side chain of leucine is affected by both urea and TMAO whereas backbone atoms and alanine's side chain are not. Urea is found to occupy positions between leucine's side chains that are not accessible to water. This accounts for extra Lennard-Jones bonds between urea and side chains that provide the enthalpic driving force for unfolding.

Inhibition properties of new amino acids for prevention of hydrate formation in carbon dioxide–water system: Experimental and modeling investigations

In the present work, the effect of new structures of amino acids is studied for prevention of hydrate formation in the carbon dioxide–water system. These amino acids consist of L-proline (as amino acid with nonpolar side chain), L-serine and L-glutamine (as amino acids with polar side chain), and L-histidine (as amino acid with charged side chain). The inhibition effects of these amino acids were compared with glycine, L-threonine, and poly-N-vinylpyrrolidone (PVP). Experiments were performed in the concentration range of 0.5–2wt.%. Investigation on the experimental results shows that inhibition properties of amino acids in an aqueous solution was due to hydrophobicity, the net charge of amino acid, and electrically charge of the side chain. Based on the experimental results, the ranking of amino acids (to decrease the hydrate growth rate) is as follows: L-histidine>glycine>L-proline≈L-serine≈L-threonine>L-glutamine, although the inhibition effect of some amino acids is not significant. In addition, the inhibition effects of these amino acids are quantitatively described by the chemical affinity model. The predicted results confirm that some of the applied amino acids decrease CO2 hydrate formation rate.