ABSTRACT
The structural dynamics involved in the mechanical flexibility of molecular crystals and the internal stress in such flexible materials remain obscure. Here, the study reports an elastically bending lipidated molecular crystal that shows systematic shifts in characteristic vibrational frequencies across the bent crystal region - revealing the nature of structural changes during bending and the local internal stress distribution. The blueshifts in the bond stretching modes (such as CâO and C-H modes) in the inner arc region and redshifts in the outer arc region of the bent crystals observed via micro-Raman mapping are counterintuitive to the bending models based on intermolecular hydrogen bonds. Correlating these shifts with the trends observed from high-pressure Raman studies on the crystal reveals the local stress difference between the inner arc and outer arc regions of the bent crystal to be ≈2 GPa, more than an order of magnitude higher than the previously proposed value in elastically bending crystals. High local internal stress can have direct ramifications on the properties of molecular piezoelectric energy harvesters, actuators, semiconductors, and flexible optoelectronic materials.
ABSTRACT
The chemical understanding of biological processes provides not only a deeper insight but also a solution to abnormal biological functioning. Protein degradation, a natural biological process for debris removal in the cell, has been studied for years. The recent finding that natural degradation pathways can be utilized for therapeutic purposes is a paradigm shift in the drug discovery approach. Methods such as Proteolysis Targeting Chimera (PROTAC), lysosomal targeting chimera, hydrophobic tagging, AUtophagy TArgeting Chimera, AUTOphagy TArgeting Chimera and several other variants of these methods have made a considerable impact on the way of drug design. Few selected examples testify that a huge wave of change is on the way. The drug design based on the targeted protein degradation is a powerful tool in our arsenal. More molecules will be invented that will uncover the hidden secrets of biological functioning and provide enduring solutions to several unmet medical needs.
ABSTRACT
[This corrects the article DOI: 10.1371/journal.pntd.0002005.].
ABSTRACT
The development of artificial molecular machines is a challenging endeavor. Herein, we have synthesized a series of bispidine diamides D1-D6 that exhibit rotation reminiscent of a motor motion. Dynamic NMR, X-ray diffraction, quantum mechanical calculations, and molecular dynamics simulations provided insights into their rotational dynamics. All the diamides D1-D6 exhibited mutually independent rotation around the two bispidine arms. However, the rate of rotation and the presence or absence of directionality in amide bond rotation were found to depend on the solvent, temperature, and nature of substitution on the amide carbonyl. These engineered systems may aid in the development of biologically relevant synthetic molecular motors. Studies on homochiral and heterochiral bispidine-peptides revealed that the direction of rotation can be controlled by chirality and the nature of the amino acid.
ABSTRACT
Intramolecular excimer formation has been utilized extensively in chemical sciences, especially to probe solvation within complex media as well as to assess physicochemical properties of the solubilizing milieu. Pyrene has been employed extensively as a fluorescence probe for this purpose due to its favorable multidimensional fluorescence properties. Termini-capped dipyrenyl scaffolds possessing various functionalities comprise the majority of such compounds. A new both end-tagged dipyrenyl compound DTP is designed and synthesized, which exhibits significantly high intramolecular excimer formation efficiency in polar solvents. The presence of a -NH-(CO)- and/or -S-S- functionality on the chain linking the two pyrenyl groups facilitates intramolecular excimer formation. Excited-state emission intensity decay reveals that the excimer formation exclusively takes place in the excited state with only one excimer conformation. The rate constant of excimer formation is found to be higher for DTP as compared to a similar compound with an alkyl backbone. The dependence of the excimer formation on the solvent (protic versus aprotic) as well as on temperature reveals further insights into the excimer formation process. The excimer formation by DTP is found to be highly sensitive to the presence of H+: the relative excimer formation efficiency decreases drastically in the presence of a small amount of H+ (â¼10-5 M). Further, the recognition of protons by DTP via intramolecular excimer formation is also observed to be highly selective in nature. Based on the observation that both the excimer formation efficiency and kinetics depend on the viscosity of the solubilizing milieu, fluidity assessment of the (dimethyl sulfoxide + acetonitrile) mixture was carried out using DTP. Further, DTP is found to be an effective probe for the assessment of the amount of water in the ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl) imide as well as in a deep eutectic solvent composed of choline chloride and urea in a 1:2 mol ratio. Highly efficient and rapid intramolecular excimer formation not only establishes DTP as a useful and versatile probe but also offers strategic pathways for designing effective excimer-forming compounds.
ABSTRACT
The development of designer topological structures is a synthetically challenging endeavor. We present herein bispidine as a platform for the design of molecules with various topologies and functions. The bispidine-based acyclic molecule, which shows intriguing S-shape topology, is discussed. Single-crystal X-ray diffraction studies revealed that this molecule exists in the solid state as two conformational enantiomers. In addition, bispidine-based designer macrocycles were synthesized and investigated for ionophoric properties. Patch clamp experiments revealed that these macrocycles transport both anions and cations non-specifically with at least tenfold higher chloride conductance over the cations under the given experimental conditions. Ultramicroscopy and single-crystal X-ray crystallographic studies indicated that the self-assembling macrocycle forms a tubular assembly. Our design highlights the use of unconventional dihydrogen interactions in nanotube fabrication.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic , Ionophores , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Biological Transport , CationsABSTRACT
Triazolophanes with larger ring sizes such as 40- and 42- were designed and synthesized. Ultramicroscopic studies on a variety of expanded triazolophanes and larger acyclic systems revealed vesicular self-assembly. The role of molecular topology on vesicular assembly was systematically investigated by studying a series of molecules with increasing curvature.
ABSTRACT
We report a novel molecular topology-based approach for creating reproducible vesicular assemblies in different solvent environments (including aqueous) using specifically designed pseudopeptides. Deviating from the classical "polar head group and hydrophobic tail" model of amphiphiles, we showed (reversible) self-assembly of synthesized pseudopeptides into vesicles. Naming these new type/class of vesicles "pseudopetosomes", we characterized them by high-resolution microscopy (scanning electron, transmission electron, atomic force, epifluorescence and confocal) along with dynamic light scattering. While accounting for hydropathy index of the constituent amino acids (side chains) of pseudopeptides, we probed molecular interactions, resulting in assembly of pseudopeptosomes by spectroscopy (fourier-transform infrared and fluorescence). Molecular characterization by X-ray crystallography and circular dichroism revealed "tryptophan (Trp)-Zip" arrangements and/or hydrogen-bonded one-dimensional assembly depending on specific pseudopeptides and solvent environments. Our data indicated that pseudopeptosomes are formed in solutions by self-assembly of bispidine pseudopeptides (of Trp, leucine and alanine amino-acid constituents) into sheets that transform into vesicular structures. Thus, we showed that assembly of pseudopeptosomes utilizes the full spectrum of all four weak interactions essential in biological systems. Our findings have direct implications in chemical and synthetic biology, but may also provide a new avenue of investigations on origins of life via pseudopeptosome-like assemblies. We also showed that these designer peptides can act as carriers for cellular transport.
Subject(s)
Amino Acids , Peptides , Amino Acids/chemistry , Peptides/chemistry , Bridged Bicyclo Compounds, Heterocyclic , Solvents/chemistry , TryptophanABSTRACT
A series of oxidized cysteinyl peptides ([P-Cys-X-OMe]2; P = Boc or H; X = Trp or Glu) showed vesicular and fibrillar assemblies. The anatomy of the self-assembled vesicles from the water-soluble cystine peptide [Cys-Trp-OMe]2 (1a) has been investigated by using various fluorescent probes such as ammonium 8-anilinonaphthalene-1-sulfonate, Nile Red and pyrene. The morphological characterization was carried out by fluorescence lifetime imaging microscopy (FLIM) and super resolution-structured illumination microscopy (SR-SIM) utilizing the autofluorescence of the vesicles stemming from the self-assembly. The self-assembled structures are also observed in solution as evident from the quantitative phase images obtained using a dual-mode digital holographic microscope (DHM) system. Present investigations show that the self-assembly is enthalpy- and entropy-driven in the aqueous medium. Based on the CD spectral studies, we proposed that 1a organizes into vesicles through the sequestration of indole units. We observed that the solutions of dipeptides 1a-b exhibit autofluorescence in the blue region upon excitation at a wavelength >350 nm. Detailed spectroscopic studies on the peptides lacking tryptophan 2a-b unequivocally showed that the autofluorescence stems exclusively from peptide aggregation. Our experimental results with appropriate controls revealed that the clustering of carbonyl chromophores is central to autofluorescence. Autofluorescence was also used to probe the vesicle formation without using any external fluorescent probe. To the best of our knowledge, this is the first report on autofluorescent vesicles formed by the spontaneous association of dipeptides. We also found that the vesicles formed by 1a can act as a host for guests like C60. The biocompatibility and biodegradability of these peptides along with the autofluorescent nature and guest binding ability of peptide-based vesicles offer numerous applications in the biomedical area.
Subject(s)
Dipeptides , Peptides , Peptides/chemistry , Microscopy, Fluorescence , Tryptophan/chemistry , Water , Fluorescent DyesABSTRACT
Liquid crystal (LC) droplets are promising candidates for sensing applications due to their high sensitivity to surface anchoring changes, resulting in readily detectable optical effects. Herein, we have designed and synthesized amino acid-based bottlebrush polymers and investigated their impact on LC director configurations in the droplets. The pseudopeptidic bottlebrush polymers with an aromatic (phenyl) and aliphatic appendages are synthesized using ring-opening metathesis polymerization (ROMP). Polymer dispersed liquid crystal (PDLC) samples are prepared by employing pseudopeptidic bottlebrush polymers and 4-cyano-4'-pentylbiphenyl (5CB) LC via solvent-induced phase separation (SIPS) technique. Due to π-π stacking, the phenyl group favours radial configuration, whereas the repulsion between 5CB and aliphatic groups induces molecular alignment leading to bipolar droplet arrangement. The impact of various pendant groups attached to the polymer on the prepared PDLC sample's surface characteristics and free energy components is illustrated. The sensing capability of 5CB dispersed in pseudopeptidic bottlebrush polymers for various pH solutions is investigated using polarizing optical microscopy (POM). The PDLC samples are moderately permeable to water and sensitive to different pH solutions. The results demonstrate a simplified and straightforward approach for preparing LC-based biosensors and chemical sensors.
Subject(s)
Liquid Crystals , Liquid Crystals/chemistry , Polymers/chemistry , Water/chemistry , Solvents , Amino AcidsABSTRACT
Here we delineate simple and tunable hydrophobically driven chiral functional assemblies of diacetylene cored pseudopeptides. These amino acid appended, rigid core dialkynes constitute promising chiral supramolecular building blocks for materials properties engineering. The chiral appended amino acid elements allow for simple tuning of solubility and interaction properties as well as governing chirality, while the central dialkyne core can impart hydrophobically driven assembly and Aggregation Induced Emission (AIE) properties. The self-assembly of these rod-like dialkynes can be regulated by tuning the solvent environment, with for example self-assembly into vesicles in acetonitrile and into helical organization with AIE in a H2 O/DMSO mixture. Of additional high interest, these supramolecular materials, themselves devoid of liquid crystal (LC) properties, can induce chirality into non-chiral LC matrices with high helical twisting power.
Subject(s)
Amino Acids , Dimethyl Sulfoxide , Acetonitriles , Hydrophobic and Hydrophilic Interactions , Solvents , StereoisomerismABSTRACT
Polymers and peptides have recently been considered as promising materials for piezoelectric energy harvesting because of their biocompatibility and enormous design possibility. However, achieving significant output voltages while meeting environmental safety requirements, low cost, and easy fabrication remains a major challenge. Herein, lipidated pseudopeptide incorporated poly(vinylidene fluoride) (PVDF) composite films are fabricated. Adding lipidated pseudopeptide (BLHA) increases the electroactive phase content, reaching the maximum for the 2 wt% composite film. The composite film containing 2 wt% BLHA manifests the highest dielectric constant and remnant polarization (Pr ), among others. A piezoelectric energy harvesting device fabricated with this film generates open-circuit output voltages up to 23 V, five times amplified output compared to pure PVDF. To the best of our knowledge, this material is superior among the peptide-based piezoelectric energy harvesters reported in the literature. The device is flexible, durable, low cost, and sensitive to high and low pressures. It can power up multiple liquid crystal display panels when pressed with a finger. The non-covalent interaction between BLHA and PVDF is the reason behind the composites' improved piezoelectric response. Density functional theory calculations also support this notion.
Subject(s)
Liquid Crystals , Peptides , Polymers , PolyvinylsABSTRACT
Molecular architecture with different fluorophoric units can offer improved and effective recognition of biologically important analytes. We present here a new strategy for the design of ratiometric chemosensors that operate by photoinduced electron transfer (PET). This ratiometric sensor endowed with tryptophan and anthracene exhibits high sensitivity, excellent selectivity and remarkable reversibility towards recognition of H+ in methanol. This "Turn-On" type behaviour is crafted into the molecule by incorporation of bispidine entity. Effective quenching of the fluorescence of the anthracene by the adjacent amine groups of the bispidine results in negligible fluorescence from the anthracene group leading to highly sensitive recognition of protons by the compound as H+ protonate the amine functionalities giving rise to the emergence of the fluorescence from the anthracene group. This, combined with the reduction in the fluorescence from the Trp group by H+, results in highly sensitive ratiometric nature of the response especially at low [H+].
Subject(s)
Anthracenes , Protons , Amines , Fluorescent Dyes , Spectrometry, Fluorescence/methodsABSTRACT
Dialysis-related amyloidosis (DRA) is considered an inescapable consequence of renal failure. Upon prolonged hemodialysis, it involves accumulation of toxic ß2-microglobulin (ß2m) amyloids in bones and joints. Current treatment methods are plagued with high cost, low specificity, and low capacity. Through our in vitro and in cellulo studies, we introduce a peptidomimetic-based approach to help develop future therapeutics against DRA. Our study reports the ability of a nontoxic, core-modified, bispidine peptidomimetic analogue "B(LVI)2" to inhibit acid-induced amyloid fibrillation of ß2m (Hß2m). Using thioflavin-T, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and transmission electron microscopy analysis, we demonstrate that B(LVI)2 delays aggregation lag time of Hß2m amyloid fibrillation and reduces the yield of Hß2m amyloid fibrils in a dose-dependent manner. Our findings suggest a B(LVI)2-orchestrated alteration in the route of Hß2m amyloid fibrillation resulting in the formation of noncytotoxic, morphologically distinct amyloid-like species. Circular dichroism data show gradual sequestration of Hß2m species in a soluble nonamyloidogenic noncytotoxic conformation in the presence of B(LVI)2. Dynamic light scattering measurements indicate incompetence of Hß2m species in the presence of B(LVI)2 to undergo amyloid-competent intermolecular associations. Overall, our study reports the antifibrillation property of a novel peptidomimetic with the potential to bring a paradigm shift in therapeutic approaches against DRA.
Subject(s)
Amyloidosis , Peptidomimetics , Amyloid , Amyloidogenic Proteins , Amyloidosis/drug therapy , Bridged Bicyclo Compounds, Heterocyclic , Humans , Peptidomimetics/pharmacology , Renal Dialysis , beta 2-MicroglobulinABSTRACT
Peptides and pseudopeptides show distinct self-assembled nanostructures such as fibers, nanotubes, vesicles, micelles, toroids, helices and rods. The formation of such molecular communities through the collective behavior of molecules is not fully understood at a molecular level. All these self-assembled nanostructured materials have a wide range of applications such as drug delivery, gene delivery, biosensing, bioimaging, catalysis, tissue engineering, nano-electronics and sensing. Self-assembly is one of the most efficient and a simple strategy to generate complex functional materials. Owing to its significance, the last few decades witnessed a remarkable advancement in the field of self-assembling peptides with a plethora of new designer synthetic systems being discovered. These systems range from amphiphilic, cyclic, linear and polymeric peptides. This article presents only selected examples of such self-assembling peptides and pseudopeptides.
Subject(s)
Nanostructures , Peptides , Nanostructures/chemistry , Peptides/chemistry , Polymers , Protein Structure, Secondary , Tissue EngineeringABSTRACT
Staphylococcus aureus is the leading cause of hospital-acquired infections. The enzyme sortase A, present on the cell surface of S. aureus, plays a key role in bacterial virulence without affecting the bacterial viability. Inhibition of sortase A activity offers a powerful but clinically less explored therapeutic strategy, as it offers the possibility of not inducing any selective pressure on the bacteria to evolve drug-resistant strains. In this Perspective, we offer a chemical space narrative for the design of sortase A inhibitors, as delineated into three broad domains: peptidomimetics, natural products, and synthetic small molecules. This provides immense opportunities for medicinal chemists to alleviate the ever-growing crisis of antibiotic resistance.
Subject(s)
Aminoacyltransferases/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Aminoacyltransferases/metabolism , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/metabolism , Bacterial Proteins/metabolism , Cell Line , Cysteine Endopeptidases/metabolism , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/metabolism , Humans , Molecular Docking Simulation , Protein Binding , Staphylococcus aureus/drug effects , Virulence/drug effectsABSTRACT
Spherical ordering from small molecules is a subject of intense interest to chemists. The inherent capability of amphiphiles to assemble spontaneously is the unique feature of the evolutionary process of life. Self-assembly is prevalent in biology and has attracted the interest of scientists across several disciplines. This is because scientists have realized that nature has extensively used this inherent organizational power contained in the molecules. Judicious use of the self-assembly principle is the cornerstone of nature's exotic assemblies. These exotic assemblies lead to unimaginable functions in biology that might not have been predicted from the monomer building blocks alone. Recently, a number of chemical systems that self-assemble in aqueous or organic solvents to form vesicles were reported. This account provides advances made from our laboratory toward designing and understanding the mechanism of formation of spherical vesicular assembly. A bottom-up approach for the de novo design of vesicles using nonlipidated molecular architecture will be a paradigm shift in vesicular research. Vesicles act as a protocell model for studying the origin and evolution of cellular life. They could also act as excellent model systems for studying the fusion of cells and membrane transport. Self-assembled vesicles have enormous potential for several applications such as drug and biomolecule delivery to cells and in materials science. These aspects along with the dynamic nature of vesicular assembly have attracted researchers to the study of spherical assemblies. The common belief was that the molecules that form vesicles must have one polar head and two hydrophobic tails. All attempts to synthesize vesicles are by mimicking nature's strategy, which mainly involves the self-assembly of lipid amphiphiles through a bilayer-like arrangement. Pseudopeptide-based molecules with the ability to form vesicles have changed this long-standing notion. In addition to chemical and medical applications, these peptide vesicles could act as models for protocells, membrane fusion, and the study of the vesiculation mechanism. This Account highlights the progress made toward a heuristic approach to the de novo design of vesicles using pseudopeptides as building blocks.A large number of diverse classes of pseudopeptides showed vesicular assembly. Various acyclic and cyclic molecules were designed and synthesized that showed spherical vesicular assembly. Cystine-based macrocyclic peptides showed drug encapsulation and release. Polymersomes with unusual topology, self-assembling tripodal ligands, and molecules containing amino acids such as lysine, leucine, cystine, and serine were synthesized. The incorporation of a wide variety of amino acids in the vesicle-forming peptides could enhance their scope and applications. The mechanism of vesiculation was also investigated using these designer molecules.
Subject(s)
Liposomes/chemistry , Peptides/chemistry , Dendrimers/chemistry , Hydrophobic and Hydrophilic Interactions , Molecular Dynamics Simulation , Polyethylene Glycols/chemistryABSTRACT
Understanding the interactions between nanoparticles and organophosphates is the key to developing cost-effective colorimetric pesticide detection. We have studied the interaction between three different organophosphates containing the P[double bond, length as m-dash]S group and borohydride stabilized silver nanoparticles. Three different organophosphates, namely phorate, chlorpyrifos, and malathion, have been used. The colorimetric changes are corroborated with UV-visible absorption studies along with the change in particle size and zeta potential. This effect persists in the presence of NaCl solution also. The chlorpyrifos and malathion do not show significant interactions with uncapped nanoparticles over time, while phorate undergoes degradation due to the scission of the S-CH2 linkage. A reaction mechanism, wherein a silver and sulfur (AgâS) complex is formed, which is in agreement with Raman spectroscopic studies is proposed. The orientations of phorate near Ag nanoparticles are discussed from the adsorption energy calculation using density functional theory.
ABSTRACT
The development of synthetic scaffolds that nucleate well-folded secondary structures is highly challenging. Herein, we designed and synthesized a series of core-modified peptides (F1, F2, F3, and F4) that fold into ß-strand structures. These bispidine-scaffolded peptides were studied by CD, IR, NMR, single crystal XRD, and Molecular Dynamics (MD) simulations to investigate their conformational preferences. Solid-state and solution studies revealed that bispidine is a versatile scaffold that could be placed either at the terminal or at the middle of the peptide strand for nucleating the ß-strand structure. Scaffolds that nucleate an isolated ß-strand conformation are rare. Bispidine placed at the C-terminus of the peptide chain could nucleate a ß-strand conformation, while bispidine placed at the middle resulted in a ß-arch conformation. This nucleation activity stems from the ability to restrict the psi torsion angle (ψ) through intramolecular C5 hydrogen bonding between the equatorial hydrogen(s) of bispidine and the carbonyl oxygen(s) of the amino acid close to the scaffold. Furthermore, the bispidine peptidomimetic with a super secondary structure, namely ß-arch, assembled into single-hole submicron cages and spherical vesicles as evident from microscopic studies. The design logic defined here will be a significant strategy for the development of ß-strand mimetics and super secondary structures.
ABSTRACT
The last few decades witnessed a remarkable advancement in the field of molecular anion receptors. A variety of anion binding motifs have been discovered, and large number of designer molecular anion receptors with high selectivity are being reported. However, anion detection in an aqueous medium is still a formidable challenge as evident from only a miniscule of synthetic systems available in the literature. We, herein, report 5,5'-dithio-bis(2-nitrobenzoic acid) (Ellman's reagent) appended with amino acids as supersensitive anion sensors that can detect F- and H2PO4- ions in both aqueous as well as organic media. Interestingly, the sensors showed a dual response to anions, viz., chromogenic response in organic medium and electrochemical response in aqueous solutions. Various spectroscopic techniques such as UV-vis and 1H NMR are used to investigate the binding studies in acetonitrile, whereas electrochemical methods such as cyclic voltammetry (CV) and differential pulse voltammetry (DPV) are employed to explore the anion binding in water. The host-guest complex stoichiometry and binding constants are calculated using the BindFit software. The geometry of host-guest complex has been optimized by the density functional theory (DFT) method. These molecules are versatile sensors since these function in both water and acetonitrile with extremely low limit of detection (LOD) up to 0.07 fM and limit of quantification (LOQ) up to 0.23 fM. To our knowledge, the present system is the first example of a sensor that can detect the lowest concentration of anions in water quantitatively. The minimalistic design strategy presented here opens up the innumerable possibilities for designing dual anion sensors in a one fell swoop.