Reactive Simulations of Silica Functionalization with Aromatic Hydrocarbons.

Reactive molecular dynamics simulations are used to model the covalent functionalization of amorphous silica with aromatic hydrocarbons. Simulations show that the surface density of silanol-terminated phenyl, naphthyl, and anthracenyl molecules is lower than the maximum value calculated based on molecule geometry, and the simulation densities decrease faster with the number of aromatic rings than the geometric densities. The trends are analyzed in terms of the surface-silanol bonding configurations, tilt angles, local conformational ordering, and aggregation of surface-bound molecules under steady-state conditions. Results show that the surface density is affected by both the size and symmetry of the aromatic hydrocarbons. The correlations among bonding, orientation, and surface density identified here may guide the selection or design of molecules for functionalized surfaces.

Photomechanochemical control over stereoselectivity in the [2 + 2] photodimerization of acenaphthylene.

Tuning solubility and mechanical activation alters the stereoselectivity of the [2 + 2] photochemical cycloaddition of acenaphthylene. Photomechanochemical conditions produce the syn cyclobutane, whereas the solid-state reaction in the absence of mechanical activation provides the anti. When the photochemical dimerization occurs in a solubilizing organic solvent, there is no selectivity. Dimerization in H2O, in which acenaphthylene is insoluble, provides the anti product. DFT calculations reveal that insoluble and solid-state reactions proceed via a covalently bonded excimer, which drives anti selectivity. Alternatively, the noncovalently bound syn conformer is more mechanosusceptible than the anti, meaning it experiences greater destabilization, thereby producing the syn product under photomechanochemical conditions. Cyclobutanes are important components of biologically active natural products and organic materials, and we demonstrate stereoselective methods for obtaining syn or anti cyclobutanes under mild conditions and without organic solvents. With this work, we validate photomechanochemistry as a viable new direction for the preparation of complex organic scaffolds.

Flexible Synthetic Carbohydrate Receptors as Inhibitors of Viral Attachment.

Carbohydrate-receptor interactions are often involved in the docking of viruses to host cells, and this docking is a necessary step in the virus life cycle that precedes infection and, ultimately, replication. Despite the conserved structures of the glycans involved in docking, they are still considered "undruggable", meaning these glycans are beyond the scope of conventional pharmacological strategies. Recent advances in the development of synthetic carbohydrate receptors (SCRs), small molecules that bind carbohydrates, could bring carbohydrate-receptor interactions within the purview of druggable targets. Here we discuss the role of carbohydrate-receptor interactions in viral infection, the evolution of SCRs, and recent results demonstrating their ability to prevent viral infections in vitro. Common SCR design strategies based on boronic ester formation, metal chelation, and noncovalent interactions are discussed. The benefits of incorporating the idiosyncrasies of natural glycan-binding proteins-including flexibility, cooperativity, and multivalency-into SCR design to achieve nonglucosidic specificity are shown. These studies into SCR design and binding could lead to new strategies for mitigating the grave threat to human health posed by enveloped viruses, which are heavily glycosylated viroids that are the cause of some of the most pressing and untreatable diseases, including HIV, Dengue, Zika, influenza, and SARS-CoV-2.

Regiochemical Effects on the Carbohydrate Binding and Selectivity of Flexible Synthetic Carbohydrate Receptors with Indole and Quinoline Heterocyclic Groups.

Synthetic carbohydrate receptors (SCRs) that bind cell-surface carbohydrates could be used for disease detection, drug-delivery, and therapeutics, or for the site-selective modification of complex carbohydrates but their potential has not been realized because of remaining challenges associated with binding affinity and substrate selectivity. We have reported recently a series of flexible SCRs based upon a biaryl core with four pendant heterocyclic groups that bind glycans selectively through noncovalent interactions. Here we continue to explore the role of heterocycles on substrate selectivity by expanding our library to include a series of indole and quinoline heterocycles that vary in their regiochemistry of attachment to the biaryl core. The binding of these SCRs to a series of biologically-relevant carbohydrates was studied by 1H NMR titrations in CD2Cl2 and density-functional theory calculations. We find SCR030, SCR034 and SCR037 are selective, SCR031, SCR032, and SCR039 are strong binders, and SCR033, SCR035, SCR036, and SCR038 are promiscuous and bind weakly. Computational analysis reveals the importance of C-H⋯π and H-bonding interactions in defining the binding properties of these new receptors. By combining these data with those obtained from our previous studies on this class of flexible SCRs, we develop a series of design rules that account for the binding of all SCRs of this class and anticipate the binding of future, not-yet imagined tetrapodal SCRs.

Glycopolymer Microarrays with Sub-Femtomolar Avidity for Glycan Binding Proteins Prepared by Grafted-To/Grafted-From Photopolymerizations.

We report a novel glycan array architecture that binds the mannose-specific glycan binding protein, concanavalin A (ConA), with sub-femtomolar avidity. A new radical photopolymerization developed specifically for this application combines the grafted-from thiol-(meth)acrylate polymerization with thiol-ene chemistry to graft glycans to the growing polymer brushes. The propagation of the brushes was studied by carrying out this grafted-to/grafted-from radical photopolymerization (GTGFRP) at >400 different conditions using hypersurface photolithography, a printing strategy that substantially accelerates reaction discovery and optimization on surfaces. The effect of brush height and the grafting density of mannosides on the binding of ConA to the brushes was studied systematically, and we found that multivalent and cooperative binding account for the unprecedented sensitivity of the GTGFRP brushes. This study further demonstrates the ease with which new chemistry can be tailored for an application as a result of the advantages of hypersurface photolithography.

Synthesis and Binding of Mannose-Specific Synthetic Carbohydrate Receptors.

Synthetic carbohydrate receptors (SCRs) that selectively recognize cell-surface glycans could be used for detection, drug delivery, or as therapeutics. Here we report the synthesis of seven new C2h symmetric tetrapodal SCRs. The structures of these SCRs possess a conserved biaryl core, and they vary in the four heterocyclic binding groups that are linked to the biaryl core via secondary amines. Supramolecular association between these SCRs and five biologically relevant C1 -O-octyloxy glycans, α/ß-glucoside (α/ß-Glc), α/ß-mannoside (α/ß-Man), and ß-galactoside (ß-Gal), was studied by mass spectrometry, 1 H NMR titrations, and molecular modeling. These studies revealed that selectivity can be achieved in these tetrapodal SCRs by varying the heterocyclic binding group. We found that SCR017 (3-pyrrole), SCR021 (3-pyridine), and SCR022 (2-phenol) bind only to ß-Glc. SCR019 (3-indole) binds only to ß-Man. SCR020 (2-pyridine) binds ß-Man and α-Man with a preference to the latter. SCR018 (2-indole) binds α-Man and ß-Gal with a preference to the former. The glycan guests bound within their SCR hosts in one of three supramolecular geometries: center-parallel, center-perpendicular, and off-center. Many host-guest combinations formed higher stoichiometry complexes, 2:1 glycan⋅SCR or 1:2 glycan⋅SCR, where the former are driven by positive allosteric cooperativity induced by glycan-glycan contacts.

Multivalent binding of concanavalin A on variable-density mannoside microarrays.

Interactions between cell surface glycans and glycan binding proteins (GBPs) have a central role in the immune response, pathogen-host recognition, cell-cell communication, and a myriad other biological processes. Because of the weak association between GBPs and glycans in solution, multivalent and cooperative interactions in the dense glycocalyx have an outsized role in directing binding affinity and selectivity. However, a major challenge in glycobiology is that few experimental approaches exist for examining and understanding quantitatively how glycan density affects avidity with GBPs, and there is a need for new tools that can fabricate glycan arrays with the ability to vary their density controllably and systematically in each feature. Here, we use thiol-ene reactions to fabricate glycan arrays using a recently developed photochemical printer that leverages a digital micromirror device and microfluidics to create multiplexed patterns of immobilized mannosides, where the density of mannosides in each feature was varied by dilution with an inert spacer allyl alcohol. The association between these immobilized glycans and FITC-labeled concanavalin A (ConA) - a tetrameric GBP that binds to mannosides multivalently - was measured by fluorescence microscopy. We observed that the fluorescence decreased nonlinearly with increasing spacer concentration in the features, and we present a model that relates the average mannoside-mannoside spacing to the abrupt drop-off in ConA binding. Applying these recent advances in microscale photolithography to the challenge of mimicking the architecture of the glycocalyx could lead to a rapid understanding of how information is trafficked on the cell surface.

Toward 4D Nanoprinting with Tip-Induced Organic Surface Reactions.

Future nanomanufacturing tools will prepare organic materials with complex four-dimensional (4D) structure, where the position (x, y, z) and chemical composition within a volume is controlled with sub-1 µm spatial resolution. Such tools could produce substrates that mimic biological interfaces, like the cell surface or the extracellular matrix, whose topology and chemical complexity combine to direct some of the most sophisticated biological events. The control of organic materials at the nanoscale-level of spatial resolution could revolutionize the assembly of next generation optical and electronic devices or substrates for tissue engineering or enable fundamental biological or material science investigations. Organic chemistry provides the requisite control over the orientation and position of matter within a nanoscale reference frame through the formation of new covalent bonds. Several challenges however preclude the integration of organic chemistry with conventional nanomanufacturing approaches, namely most nanolithography platforms would denature or destroy delicate organic and biologically active matter, confirming covalent bond formation at interfaces remains difficult, and finally, only a small handful of the reactions used to transform molecules in solution have been validated on surfaces. Thus, entirely new approaches, where organic transformations and spatial control are considered equally important contributors, are needed to create 4D organic nanoprinting platforms. This Account describes efforts from our group to reconcile nanolithography, and specifically massively parallel scanning probe lithography (SPL), with organic chemistry to further the goal of 4D organic nanoprinting. Massively parallel SPL involves arrays of elastomeric pyramids mounted onto piezoelectric actuators, and creates patterns with feature diameters below 50 nm by using the pyramidal tips for either the direct deposition of ink or the localized delivery of energy to a surface. While other groups have focused on tip and array architetctures, our efforts have been on exploring their use for localizing organic chemistry on surfaces with nanoscale spatial resolution in 3D. Herein we describe the use of massively parallel SPL to create covalently immobilized patterns of organic materials using thermal, catalytic, photochemical, and force-accelerated reactions. In doing so, we have developed a high-throughput protocol for confirming interfacial bond formation. These efforts have resulted in new opportunities for the preparation of glycan arrays, novel approaches for covalently patterning graphene, and a 3D nanoprinter by combining photochemical brush polymerizations with SPL. Achieving true 4D nanoprinting involves advances in surface chemistry and instrumentation development, and to this end 4D micropatterns were produced in a microfluidic photoreactor that can position polymers composed of different monomers within micrometer proximity. A substantial gap remains, however, between these current technologies and the future's 4D nanomanufacturing tools, but the marriage of SPL with organic chemistry is an important step toward this goal. As this field continues to mature we can expect bottom-up 4D nanomanufacturing to begin supplanting conventional top-down strategies for preparing electronics, bioarrays, and functional substrates. In addition, these new printing technologies may enable the preparation of synthetic targets, such as artificial biological interfaces, with a level of organic sophistication that is entirely unachievable using existing technologies.

Binding Studies on a Library of Induced-Fit Synthetic Carbohydrate Receptors with Mannoside Selectivity.

Synthetic carbohydrate receptors could serve as agents for disease detection, drug delivery, or even therapeutics, however, they are rarely used for these applications because they bind weakly and with a preference towards the all-equatorial glucosides that are not prevalent on the cell surface. Herein the binding of 8 receptors with 5 distinct octyloxy pyranosides, which was measured by mass spectrometry and by 1 H NMR titrations in CD2 Cl2 at 298 K, is reported, providing binding affinities that vary from ≈101 -104 m-1 . Although the receptors are promiscuous, 1 shows selectivity for ß-Man at a ratio of 103:1 ß-Man:ß-Gal, receptors 2-4 and 6 have preference for α-Man, 5 is selective for ß-Gal, and 10 prefers α-Glc (Man=mannose; Gal=galactose, Glc=glucose). A variety of 1D and 2D NMR, and computational techniques were used to determine the thermodynamic binding parameters (ΔHo and ΔSo ) and the structure of the host-guest complex, revealing that dimeric receptor 10 binds ß-Man with increased enthalpy, but a larger entropic penalty than 1. The first-principles modelling suggests that 10⋅ß-Man forms an inclusion-type complex where the glycan engages both monomeric subunits of 10 through H-bonding and C-H⋅⋅⋅π interactions. Like natural glycan-binding proteins, these receptors bind pyranosides by accessing multivalent and cooperative interactions, and these studies suggest a new approach towards biomimetic synthetic carbohydrate receptors, where conformational flexibility and promiscuity are incorporated into design.

Hard-tip, soft-spring lithography.

Nanofabrication strategies are becoming increasingly expensive and equipment-intensive, and consequently less accessible to researchers. As an alternative, scanning probe lithography has become a popular means of preparing nanoscale structures, in part owing to its relatively low cost and high resolution, and a registration accuracy that exceeds most existing technologies. However, increasing the throughput of cantilever-based scanning probe systems while maintaining their resolution and registration advantages has from the outset been a significant challenge. Even with impressive recent advances in cantilever array design, such arrays tend to be highly specialized for a given application, expensive, and often difficult to implement. It is therefore difficult to imagine commercially viable production methods based on scanning probe systems that rely on conventional cantilevers. Here we describe a low-cost and scalable cantilever-free tip-based nanopatterning method that uses an array of hard silicon tips mounted onto an elastomeric backing. This method-which we term hard-tip, soft-spring lithography-overcomes the throughput problems of cantilever-based scanning probe systems and the resolution limits imposed by the use of elastomeric stamps and tips: it is capable of delivering materials or energy to a surface to create arbitrary patterns of features with sub-50-nm resolution over centimetre-scale areas. We argue that hard-tip, soft-spring lithography is a versatile nanolithography strategy that should be widely adopted by academic and industrial researchers for rapid prototyping applications.

Towards scanning probe lithography-based 4D nanoprinting by advancing surface chemistry, nanopatterning strategies, and characterization protocols.

Biointerfaces direct some of the most complex biological events, including cell differentiation, hierarchical organization, and disease progression, or are responsible for the remarkable optical, electronic, and biological behavior of natural materials. Chemical information encoded within the 4D nanostructure of biointerfaces - comprised of the three Cartesian coordinates (x, y, z), and chemical composition of each molecule within a given volume - dominates their interfacial properties. As such, there is a strong interest in creating printing platforms that can emulate the 4D nanostructure - including both the chemical composition and architectural complexity - of biointerfaces. Current nanolithography technologies are unable to recreate 4D nanostructures with the chemical or architectural complexity of their biological counterparts because of their inability to position organic molecules in three dimensions and with sub-1 micrometer resolution. Achieving this level of control over the interfacial structure requires transformational advances in three complementary research disciplines: (1) the scope of organic reactions that can be successfully carried out on surfaces must be increased, (2) lithography tools are needed that are capable of positioning soft organic and biologically active materials with sub-1 micrometer resolution over feature diameter, feature-to-feature spacing, and height, and (3) new techniques for characterizing the 4D structure of interfaces should be developed and validated. This review will discuss recent advances in these three areas, and how their convergence is leading to a revolution in 4D nanomanufacturing.

Reactions in elastomeric nanoreactors reveal the role of force on the kinetics of the Huisgen reaction on surfaces.

The force dependence of the copper-free Huisgen cycloaddition between an alkyne and a surface-bound azide was examined in elastomeric nanoreactors. These studies revealed that pressure and chain length are critical factors that determine the reaction rate. These experiments demonstrate the central role of pressure and surface structure on interfacial processes that are increasingly important in biology, materials science, and nanotechnology.

Cooperatively assembling donor-acceptor superstructures direct energy into an emergent charge separated state.

A novel supramolecular system composed of diketopyrrolopyrrole electron donors and perylene derived bisimide (PDI) electron acceptors forms superstructures that undergo fast photoinduced charge separation following assembly. This bioinspired route toward functional hierarchical structures, whereby assembly and electronic properties are closely coupled, could lead to new materials for artificial photosynthesis and organic electronics.

Hydrodynamic capture of microswimmers into sphere-bound orbits.

Self-propelled particles can exhibit surprising non-equilibrium behaviors, and how they interact with obstacles or boundaries remains an important open problem. Here we show that chemically propelled micro-rods can be captured, with little change in their speed, into close orbits around solid spheres resting on or near a horizontal plane. We show that this interaction between sphere and particle is short-range, occurring even for spheres smaller than the particle length, and for a variety of sphere materials. We consider a simple model, based on lubrication theory, of a force- and torque-free swimmer driven by a surface slip (the phoretic propulsion mechanism) and moving near a solid surface. The model demonstrates capture, or movement towards the surface, and yields speeds independent of distance. This study reveals the crucial aspects of activity­driven interactions of self-propelled particles with passive objects, and brings into question the use of colloidal tracers as probes of active matter.