Chain stretching in brushes favors sequence recognition for nucleobase-functionalized flexible precise oligomers.

Six different flexible stereocontrolled oligo(triazole-urethane)s substituted by precise sequences of nucleobases or analogs are synthesized. Molecular dynamics simulations indicate that the flexibility of the backbone leads to unspecific complexation of pairs of oligomers, irrespective of the complementarity of their sequences. This is ascribed to the existence of other interactions between pairs of oligomers, as well as to the spatial blurring of the sequence order encoded in the chemical structure of the chain due to its flexibility. The same conclusions are drawn when investigating the irreversible adsorption of different probe oligomers onto a layer of target oligomers grafted by click chemistry in a mushroom configuration on a silicon substrate. In contrast, when the target oligomers are grafted in denser brush configurations, irreversible adsorption becomes more specific, with it being twice as probable that probe chains of complementary sequence would be irreversibly-bound to the layer of target chains than those of non-complementary sequence. This is ascribed to lateral excluded volume interactions between chains in the brush, leading to partial chain stretching and increased spatial preservation of the information contained in the monomer sequence of the chains. At even higher grafting densities, however, the penetration of the probe chains in the brush becomes increasingly difficult, resulting in a loss of binding efficiency. Our work thus demonstrates the adverse role of chain flexibility in the specificity of complexation between nucleobase-functionalized oligomers and provides directions for an improvement of specificity by tuning the grafting density of target chains on a substrate.

Towards a Rational Design of Antibody-Recruiting Molecules through a Computational Microscopy View of their Interactions with the Target Antibody.

Antibody recruiting molecules (ARMs) are an innovative class of chimeric molecules, consisting of an antibody-binding ligand (ABL) and a target-binding ligand (TBL). ARMs mediate ternary complex formation between a target cell of interest for elimination and endogenous antibodies that are present in human serum. Clustering of fragment crystallizable (Fc) domains on the surface of antibody-bound cells mediate destruction of the target cell by innate immune effector mechanisms. ARMs are typically designed by conjugating small molecule haptens to a (macro)molecular scaffold, without considering the structure of the respective anti-hapten antibody. Here we report on a computational molecular modeling methodology that allows for studying the close contacts between ARMs and the anti-hapten antibody, considering (1) the spacer length between ABL and TBL; (2) the number of ABL and TBL, and (3) the molecular scaffold onto which these are positioned. Our model predicts the difference in binding modes of the ternary complex and predicts which ARMs are optimal recruiters. Avidity measurements of the ARM-antibody complex and ARM-mediated antibody recruitment to cell surfaces in vitro confirmed these computational modeling predictions. This kind of multiscale molecular modelling holds potential for design of drug molecules that rely on antibody binding for their mechanism of action.

Gaining Insights on the Interactions of a Class of Decorated (2-([2,2'-Bipyridin]-6-yl)phenyl)platinum Compounds with c-Myc Oncogene Promoter G-Quadruplex and Other DNA Structures.

Organometallic molecules offer some of the most promising scaffolds for interaction with G-quadruplex nucleic acids. We report the efficient synthesis of a family of organoplatinum(II) complexes, featuring a 2-([2,2'-bipyridin]-6-yl)phenyl tridentate (N∧ N∧ C) ligand, that incorporates peripheral side-chains aiming at enhancing and diversifying its interaction capabilities. These include a di-isopropyl carbamoyl amide, a morpholine ethylenamide, two enantiomeric proline imides and an oxazole. The binding affinities of the Pt-complexes were evaluated via UV-vis and fluorescence titrations, against 5 topologically-distinct DNA structures, including c-myc G-quadruplex, two telomeric (22AG) G-quadruplexes, a duplex (ds26) and a single-stranded (polyT) DNA. All compounds exhibited binding selectivity in favour of c-myc, with association constants (Ka ) in the range of 2-5×105  M-1 , lower affinity for both folds of 22AG and for ds26 and negligible affinity for polyT. Remarkable emission enhancements (up to 200-fold) upon addition of excess DNA were demonstrated by a subset of the compounds with c-myc, providing a basis for optical selectivity, since optical response to all other tested DNAs was low. A c-myc DNA-melting experiment showed significant stabilizing abilities for all compounds, with the most potent binder, the morpholine-Pt-complex, exhibiting a ΔTm >30 °C, at 1 : 5 DNA-to-ligand molar ratio. The same study implied contributions of the diverse side-chains to helix stabilization. To gain direct evidence of the nature of the interactions, mixtures of c-myc with the four most promising compounds were studied via UV Resonance Raman (UVRR) spectroscopy, which revealed end-stacking binding mode, combined with interactions of side-chains with loop nucleobase residues. Docking simulations were conducted to provide insights into the binding modes for the same four Pt-compounds, suggesting that the binding preference for two alternative orientations of the c-myc G-quadruplex thymine 'cap' ('open' vs. 'closed'), as well as the relative contributions to affinity from end-stacking and H-bonding, are highly dependent on the nature of the interacting Pt-complex side-chain.

Hierarchical Self-Assembly and Multidynamic Responsiveness of Fluorescent Dynamic Covalent Networks Forming Organogels.

Smart stimuli-responsive fluorescent materials are of interest in the context of sensing and imaging applications. In this project, we elaborated multidynamic fluorescent materials made of a tetraphenylethene fluorophore displaying aggregation-induced emission and short cysteine-rich C-hydrazide peptides. Specifically, we show that a hierarchical dynamic covalent self-assembly process, combining disulfide and acyl-hydrazone bond formation operating simultaneously in a one-pot reaction, yields cage compounds at low concentration (2 mM), while soluble fluorescent dynamic covalent networks and even chemically cross-linked fluorescent organogels are formed at higher concentrations. The number of cysteine residues in the peptide sequence impacts directly the mechanical properties of the resulting organogels, Young's moduli varying 2500-fold across the series. These materials underpinned by a nanofibrillar network display multidynamic responsiveness following concentration changes, chemical triggers, as well as light irradiation, all of which enable their controlled degradation with concomitant changes in spectroscopic outputs─self-assembly enhances fluorescence emission by ca. 100-fold and disassembly quenches fluorescence emission.

Revealing the Organization of Catalytic Sequence-Defined Oligomers via Combined Molecular Dynamics Simulations and Network Analysis.

Similar to biological macromolecules such as DNA and proteins, the precise control over the monomer position in sequence-defined polymers is of paramount importance for tuning their structures and properties toward achieving specific functions. Here, we apply molecular network analysis on three-dimensional structures issued from molecular dynamics simulations to decipher how the chain organization of trifunctional catalytic oligomers is influenced by the oligomer sequence and the length of oligo(ethylene oxide) spacers. Our findings demonstrate that the tuning of their primary structures is crucial for favoring cooperative interactions between the catalytic units and thus higher catalytic activities. This combined approach can assist in establishing structure-property relationships, leading to a more rational design of sequence-defined catalytic oligomers via computational chemistry.

Fluorescent Dynamic Covalent Polymers for DNA Complexation and Templated Assembly.

Dynamic covalent polymers (DCPs) offer opportunities as adaptive materials of particular interest for targeting, sensing and delivery of biological molecules. In this view, combining cationic units and fluorescent units along DCP chains is attractive for achieving optical probes for the recognition and delivery of nucleic acids. Here, we report on the design of acylhydrazone-based DCPs combining cationic arginine units with π-conjugated fluorescent moieties based on thiophene-ethynyl-fluorene cores. Two types of fluorescent building blocks bearing neutral or cationic side groups on the fluorene moiety are considered in order to assess the role of the number of cationic units on complexation with DNA. The (chir)optical properties of the building blocks, the DCPs, and their complexes with several types of DNA are explored, providing details on the formation of supramolecular complexes and on their stability in aqueous solutions. The DNA-templated formation of DCPs is demonstrated, which provides new perspectives on the assembly of fluorescent DCP based on the nucleic acid structure.

Naphthodithiophene Diimide Based Chiral π-Conjugated Nanopillar Molecules.

The synthesis, structures, and properties of [4]cyclonaphthodithiophene diimides ([4]C-NDTIs) are described. NDTIs as important n-type building blocks were catenated in the α-positions of thiophene rings via an unusual electrochemical-oxidation-promoted macrocyclization route. The thiophene-thiophene junction in [4]C-NDTIs results in an ideal pillar shape. This interesting topology, along with appealing electronic and optical properties inherited from the NDTI units, endows the [4]C-NDTIs with both near-infrared (NIR) light absorptions, strong excitonic coupling, and tight encapsulation of C60 . Stable orientations of the NDTI units in the nanopillars lead to stable inherent chirality, which enables detailed circular dichroism studies on the impact of isomeric structures on π-conjugation. Remarkably, the [4]C-NDTIs maintain the strong π-π stacking abilities of NDTI units and thus adopt two-dimensional (2D) lattice arrays at the molecular level. These nanopillar molecules have great potential to mimic natural photosynthetic systems for the development of multifunctional organic materials.

Programmed Recognition between Complementary Dinucleolipids To Control the Self-Assembly of Lipidic Amphiphiles.

One of the major goals in systems chemistry is to create molecular assemblies with emergent properties that are characteristic of life. An interesting approach toward this goal is based on merging different biological building blocks into synthetic systems with properties arising from the combination of their molecular components. The covalent linkage of nucleic acids (or their constituents: nucleotides, nucleosides and nucleobases) with lipids in the same hybrid molecule leads, for example, to the so-called nucleolipids. Herein, we describe nucleolipids with a very short sequence of two nucleobases per lipid, which, in combination with hydrophobic effects promoted by the lipophilic chain, allow control of the self-assembly of lipidic amphiphiles to be achieved. The present work describes a spectroscopic and microscopy study of the structural features and dynamic self-assembly of dinucleolipids that contain adenine or thymine moieties, either pure or in mixtures. This approach leads to different self-assembled nanostructures, which include spherical, rectangular and fibrillar assemblies, as a function of the sequence of nucleobases and chiral effects of the nucleolipids involved. We also show evidence that the resulting architectures can encapsulate hydrophobic molecules, revealing their potential as drug delivery vehicles or as compartments to host interesting chemistries in their interior.

Binding Mode Multiplicity and Multiscale Chirality in the Supramolecular Assembly of DNA and a π-Conjugated Polymer.

Water-soluble π-conjugated polymers are increasingly considered for DNA biosensing. However, the conformational rearrangement, supramolecular organization and dynamics upon interaction with DNA have been overlooked, which prevents the rational design of such detection tools. To elucidate the binding of a cationic polythiophene (CPT) to DNA with atomistic resolution, we performed molecular simulations of their supramolecular assembly. Comparison of replicated simulations show a multiplicity of CPT binding geometries that contribute to the wrapping of CPT around DNA. The different binding geometries are stabilized by both electrostatic interactions between CPT lateral cations and DNA phosphodiesters and van der Waals interactions between the CPT backbone and the DNA grooves. Simulated circular dichroism (CD) spectra show that the induced CD signal stems from a conserved geometrical feature across the replicated simulations, i. e. the presence of segments of syn configurations between thiophene units along the CPT chain. At the macromolecular scale, we inspected the different shapes related to the CPT binding modes around the DNA through symmetry metrics. Altogether, molecular dynamics (MD) simulations, model Hamiltonian calculations of the CD spectra, and symmetry indices provide insights into the origin of induced chirality from the atomic to the macromolecular scale. Our multidisciplinary approach points out the hierarchical aspect of CPT chiral organization induced by DNA.

In Depth Analysis of Photovoltaic Performance of Chlorophyll Derivative-Based "All Solid-State" Dye-Sensitized Solar Cells.

Chlorophyll a derivatives were integrated in "all solid-state" dye sensitized solar cells (DSSCs) with a mesoporous TiO2 electrode and 2',2',7,7'-tetrakis[N,N-di(4-methoxyphenyl)amino]-9,9'-spirobifluorene as the hole-transport material. Despite modest power conversion efficiencies (PCEs) between 0.26% and 0.55% achieved for these chlorin dyes, a systematic investigation was carried out in order to elucidate their main limitations. To provide a comprehensive understanding of the parameters (structure, nature of the anchoring group, adsorption …) and their relationship with the PCEs, density functional theory (DFT) calculations, optical and photovoltaic studies and electron paramagnetic resonance analysis exploiting the 4-carboxy-TEMPO spin probe were combined. The recombination kinetics, the frontier molecular orbitals of these DSSCs and the adsorption efficiency onto the TiO2 surface were found to be the key parameters that govern their photovoltaic response.

Binding Modes and Selectivity of Ruthenium Complexes to Human Telomeric DNA G-Quadruplexes.

Metal complexes constitute an important class of DNA binders. In particular, a few ruthenium polyazaaromatic complexes are attractive as "light switches" because of their strong luminescence enhancement upon DNA binding. In this paper, a comprehensive study on the binding modes of several mononuclear and binuclear ruthenium complexes to human telomeric sequences, made of repeats of the d(TTAGGG) fragment is reported. These DNA sequences form G-quadruplexes (G4s) at the ends of chromosomes and constitute a relevant biomolecular target in cancer research. By combining spectroscopy experiments and molecular modelling simulations, several key properties are deciphered: the binding modes, the stabilization of G4 upon binding, and the selectivity of these complexes towards G4 versus double-stranded DNA. These results are rationalized by assessing the possible deformation of G4 and the binding free energies of several binding modes via modelling approaches. Altogether, this comparative study provides fundamental insights into the molecular recognition properties and selectivity of Ru complexes towards this important class of DNA G4s.

Photomodulation of DNA-Templated Supramolecular Assemblies.

A new type of DNA ligand that contains a phosphate-binding group and a photoresponsive azobenzene moiety is reported. When the azobenzene is in trans configuration, the ligand binds to the minor groove of a double-stranded DNA, whereas it partially desorbs upon trans-cis isomerisation with light. The ability to photoswitch the ligand upon interaction with DNA is evidenced by (chir)optical signatures, and deciphered by the differences of binding geometry, stability, and dynamics of the DNA/ligand complexes for the two isomers. We exploit these properties to photomodulate DNA-templated self-assembly, through the incorporation of another π-stacking DNA ligand, which together with the photoresponsive ligand form mixed supramolecular complexes along DNA. Our study demonstrates that well-designed photoresponsive DNA binders can be used to modulate multicomponent supramolecular DNA assemblies.

Self-assembly and chiroptical properties in supramolecular complexes of adenosine phosphates and guanidinium-bispyrene.

Supramolecular systems that respond to the hydrolysis of adenosine phosphates (APs) are attractive for biosensing and to fabricate bioinspired self-assembled materials. Here, we report on the formation of supramolecular complexes between an achiral guanidinium derivative bearing two pyrene moieties, with each of the three adenosine phosphates: AMP, ADP, and ATP. By combining results from circular dichroism spectroscopy and molecular modeling simulations, we explore the induced chirality, the dynamics of the complexes, and the interactions at play, which altogether provide insights into the supramolecular self-assembly between APs and the guanidinium-bispyrene. Finally, we identify the chiroptical signals of interest in mixtures of the guanidinium derivative with the three APs in different proportions. This study constitutes a basis to evolve toward a chiroptical detection of the hydrolysis of APs based on organic supramolecular probes.

Synthesis and photophysical studies of a multivalent photoreactive RuII-calix[4]arene complex bearing RGD-containing cyclopentapeptides.

Photoactive ruthenium-based complexes are actively studied for their biological applications as potential theragnostic agents against cancer. One major issue of these inorganic complexes is to penetrate inside cells in order to fulfil their function, either sensing the internal cell environment or exert a photocytotoxic activity. The use of lipophilic ligands allows the corresponding ruthenium complexes to passively diffuse inside cells but limits their structural and photophysical properties. Moreover, this strategy does not provide any cell selectivity. This limitation is also faced by complexes anchored on cell-penetrating peptides. In order to provide a selective cell targeting, we developed a multivalent system composed of a photoreactive ruthenium(II) complex tethered to a calix[4]arene platform bearing multiple RGD-containing cyclopentapeptides. Extensive photophysical and photochemical characterizations of this Ru(II)-calixarene conjugate as well as the study of its photoreactivity in the presence of guanosine monophosphate have been achieved. The results show that the ruthenium complex should be able to perform efficiently its photoinduced cytotoxic activity, once incorporated into targeted cancer cells thanks to the multivalent platform.

Origin of DNA-Induced Circular Dichroism in a Minor-Groove Binder.

Induced circular dichroism (ICD) of DNA-binding ligands is well known to be strongly influenced by the specific mode of binding, but the relative importance of the possible mechanisms has remained undetermined. With a combination of molecular dynamics simulations, CD response calculations, and experiments on an AT-sequence, we show that the ICD of minor-groove-bound 4',6-diamidino-2-phenylindole (DAPI) originates from an intricate interplay between the chiral imprint of DNA, off-resonant excitonic coupling to nucleobases, charge-transfer, and resonant excitonic coupling between DAPIs. The significant contributions from charge-transfer and the chiral imprint to the ICD demonstrate the inadequacy of a standard Frenkel exciton theory of the DAPI-DNA interactions.

One-Pot Self-Assembly of Peptide-Based Cage-Type Nanostructures Using Orthogonal Ligations.

The designed arrangement of biomolecular entities within monodisperse nanostructures is an important challenge toward functional biomaterials. We report herein a method for the formation of water-soluble peptide-based cages using orthogonal ligation reactions-acylhydrazone condensation and thiol-maleimide addition. The results show that using preorganized cyclic peptides and heterobifunctional spacers as building blocks and a set of orthogonal and chemoselective ligation reactions enable cage formation in one pot from six components and through eight reactions. Molecular modelling simulations reveal the structural dynamics of these structures. Finally, we exploited the reactional dynamics of the acylhydrazone by demonstrating the controlled dissociation of the cage through directed component exchange.

Solvent Molding of Organic Morphologies Made of Supramolecular Chiral Polymers.

The self-assembly and self-organization behavior of uracil-conjugated enantiopure (R)- or (S)-1,1'-binaphthyl-2,2'-diol (BINOL) and a hydrophobic oligo(p-phenylene ethynylene) (OPE) chromophore exposing 2,6-di(acetylamino)pyridine termini are reported. Systematic spectroscopic (UV-vis, CD, fluorescence, NMR, and SAXS) and microscopic studies (TEM and AFM) showed that BINOL and OPE compounds undergo triple H-bonding recognition, generating different organic nanostructures in solution. Depending on the solvophobic properties of the liquid media (toluene, CHCl3, CHCl3/CHX, and CHX/THF), spherical, rod-like, fibrous, and helical morphologies were obtained, with the latter being the only nanostructures expressing chirality at the microscopic level. SAXS analysis combined with molecular modeling simulations showed that the helical superstructures are composed of dimeric double-cable tape-like structures that, in turn, are supercoiled at the microscale. This behavior is interpreted as a consequence of an interplay among the degree of association of the H-bonded recognition, the vapor pressure of the solvent, and the solvophobic/solvophilic character of the supramolecular adducts in the different solutions under static and dynamic conditions, namely solvent evaporation conditions at room temperature.

Fiber-Optic SPR Immunosensors Tailored To Target Epithelial Cells through Membrane Receptors.

We report, for the first time, the use of a surface plasmon resonance (SPR) fiber-optic immunosensor for selective cellular detection through membrane protein targeting. The sensor architecture lies on gold-coated tilted fiber Bragg gratings (Au-coated TFBGs) photoimprinted in the fiber core via a laser technique. TFBGs operate in the near-infrared wavelength range at ∼1550 nm, yielding optical and SPR sensing characteristics that are advantageous for the analyses of cellular bindings and technical compatibility with relatively low-cost telecommunication-grade measurement devices. In this work, we take consider their numerous assets to figure out their ability to selectively detect intact epithelial cells as analytes in cell suspensions in the range of 2-5 × 10(6) cells mL(-1). For this, the probe was first thermally annealed to ensure a strong adhesion of the metallic coating to the fiber surface. Its surface was then functionalized with specific monoclonal antibodies via alkanethiol self-assembled monolayers (SAMs) against extracellular domain of epidermal growth factor receptors (EGFRs) and characterized by peak force tapping atomic force microscopy. A differential diagnosis has been demonstrated between two model systems. The developed immunosensors were able to monitor, in real time, the specific attachment of single intact cells in concentrations from 3 × 10(6) cells mL(-1). Such results confirm that the developed probe fits the lab-on-fiber technology and has the potential to be used as a disposable device for in situ and real-time clinical diagnosis.

Parameters influencing the photo-induced electron transfer from tryptophan-containing peptides to a Ru(II) complex: a systematic study.

Ruthenium(II) polyazaaromatic complexes have gained interest in recent decades as biomolecular tools, especially in the development of new phototherapeutic agents. These light emissive Ru complexes based on π-deficient ligands were first designed to allow a photo-induced electron transfer (PET) with the guanine base in DNA since their (3)MLCT state is highly photo-oxidizing. Later the field of research was extended to proteins with the highlighting of a PET process with the tryptophan residue. This paper reports the kinetics of the luminescence quenching of [Ru(TAP)2phen](2+) by several selected peptide sequences containing at least one tryptophan residue. By using a peptide library we highlight the important parameters influencing the kinetics of the photo-electron transfer process, such as the net electrostatic charge and the number of tryptophan residues. The best peptide candidates were selected to study the formation of photo-products by MALDI-ToF mass spectrometry. A high photoreactivity of the [Ru(TAP)2phen](2+) complex was observed and multiple photoadducts were characterized, among them inter-peptidic adducts as well as intra-peptidic adducts.

Self-assembly and hybridization mechanisms of DNA with cationic polythiophene.

The combination of DNA and π-conjugated polyelectrolytes (CPEs) represents a promising approach to develop DNA hybridization biosensors, with potential applications for instance in the detection of DNA lesions and single-nucleotide polymorphisms. Here we exploit the remarkable optical properties of a cationic poly[3-(6'-(trimethylphosphonium)hexyl)thiophene-2,5-diyl] (CPT) to decipher the self-assembly of DNA and CPT. The ssDNA/CPT complexes have chiroptical signatures in the CPT absorption region that are strongly dependent on the DNA sequence, which we relate to differences in supramolecular interactions between the thiophene monomers and the various nucleobases. By studying DNA-DNA hybridization and melting processes on preformed ssDNA/CPT complexes, we observe sequence-dependent mechanisms that can yield DNA-condensed aggregates. Heating-cooling cycles show that non-equilibrium mixtures can form, noticeably depending on the working sequence of the hybridization experiment. These results are of high importance for the use of π-conjugated polyelectrolytes in DNA hybridization biosensors and in polyplexes.