Multicomponent Assembly Research Articles

Optimal procurement strategies for contractual assembly systems with fluctuating procurement price

We consider a multi-component assembly system that produces a single end product in order to satisfy the one-time demand at a (known) future time with an exogenous selling price. Components can be outsourced from outside suppliers with positive leadtimes under either time-inflexible or time-flexible contracts. One of these components, say component 1, faces an uncertainty in its procurement price, depending on the spot market price that is governed by a geometric Brownian motion, while the prices of other components are constant. Given supply contracts, the assembler needs to determine the procurement strategy to maximize the total expected profit that equals the expected revenue minus procurement cost, holding cost, and tardiness penalty cost. Under time-inflexible contracts, the problem is static and a variant of the classic newsvendor problem. We show that leadtime uncertainty will cause the assembler to be more conservative in procurement quantity, but more aggressive in procurement timing than if the leadtime is deterministic. For time-flexible contracts, we show that under certain conditions, the original problem is equivalent to an optimal single stopping problem whose optimal strategies follow either upward or downward base-price procurement policies. Under the general condition, we propose an efficient Monte Carlo simulation method to calculate the optimal solutions. Numerical studies also provide several interesting insights: first, both procurement quantity and profit are non-monotone in the leadtime length; second, the value of time-flexible contracts compared to time-inflexible contracts is close to zero if the price of component 1 has a decreasing trend, but otherwise significant.

Understanding the impacts of missense mutations on structures and functions of human cancer-related genes: A preliminary computational analysis of the COSMIC Cancer Gene Census.

Genomics and genome screening are proving central to the study of cancer. However, a good appreciation of the protein structures coded by cancer genes is also invaluable, especially for the understanding of functions, for assessing ligandability of potential targets, and for designing new drugs. To complement the wealth of information on the genetics of cancer in COSMIC, the most comprehensive database for cancer somatic mutations available, structural information obtained experimentally has been brought together recently in COSMIC-3D. Even where structural information is available for a gene in the Cancer Gene Census, a list of genes in COSMIC with substantial evidence supporting their impacts in cancer, this information is quite often for a single domain in a larger protein or for a single protomer in a multiprotein assembly. Here, we show that over 60% of the genes included in the Cancer Gene Census are predicted to possess multiple domains. Many are also multicomponent and membrane-associated molecular assemblies, with mutations recorded in COSMIC affecting such assemblies. However, only 469 of the gene products have a structure represented in the PDB, and of these only 87 structures have 90–100% coverage over the sequence and 69 have less than 10% coverage. As a first step to bridging gaps in our knowledge in the many cases where individual protein structures and domains are lacking, we discuss our attempts of protein structure modelling using our pipeline and investigating the effects of mutations using two of our in-house methods (SDM2 and mCSM) and identifying potential driver mutations. This allows us to begin to understand the effects of mutations not only on protein stability but also on protein-protein, protein-ligand and protein-nucleic acid interactions. In addition, we consider ways to combine the structural information with the wealth of mutation data available in COSMIC. We discuss the impacts of COSMIC missense mutations on protein structure in order to identify and assess the molecular consequences of cancer-driving mutations.

Organocatalytic Mukaiyama Mannich Reactions of 2,5-Bis(trimethylsilyloxy)furan.

The organocatalytic synthesis of densely substituted mono- and bis-γ-lactams involving the Mukaiyama Mannich addition of 2,5-bis(trimethylsilyloxy)furan to imines is described. Use of a ditoluenesulfonylimide catalyst produces γ-lactams from monoaddition, whereas a more acidic catalyst (triflic acid) produces fused bis-lactams from double addition. Optimized organocatalytic conditions allow for the selective synthesis of either desired core as well as the one-pot, multicomponent assembly of the trisubstituted monolactams from aldehydes, amines, and bis-trimethylsilyloxyfuran. An examination of chiral acids found these organocatalysts to be highly active and diastereoselective in the monoaddition reaction, albeit with no enantioselectivity.

Zn-Catalyzed Multicomponent KA2 Coupling: One-Pot Assembly of Propargylamines Bearing Tetrasubstituted Carbon Centers

Tetrasubstituted propargylamines comprise a unique class of highly useful compounds, which can be accessed through the multicomponent coupling between ketones, amines, and alkynes (KA2 coupling), an underexplored transformation. Herein, the development of a novel, highly efficient, and user-friendly catalytic system for the KA2 coupling, based on the environmentally benign, inexpensive, and readily available zinc acetate, is described. This system is employed in the multicomponent assembly of unprecedented, tetrasubstituted propargylamines derived from structurally diverse, challenging, and even biorelevant substrates. Notable features of this protocol include the demonstration of the enhancing effect that neat conditions can have on catalytic activity, as well as the expedient functionalization of hindered, prochiral cyclohexanones, linear ketones, and interesting molecular scaffolds such as norcamphor and nornicotine.

Multi-component luminescence responsive Eu3+/Tb3+ hybrids based with metal-organic frameworks and zeolites A.

Both Zeolite A (ZA) and two kinds of 2,2'-bipyridine-5,5'-dicarboxylic acid (H2bpydc) linking meta-organic frameworks (MOFs) (MOF-253 (Al(OH)(bpydc)) and UiO-67 ([Zr6O4(OH)4(bpydc)6])) have been used to construct novel photofunctional multi-component lanthanide hybrid materials through covalent-coordination cooperative assembly. Microporous ZA is firstly functionalized by covalently grafting of the surface hydroxyl groups using special silane crosslinking reagent 3-methacryloxypropyltrimethoxysilane (MPTMS). Then the multi-component assembly are realized by coordination interaction between lanthanide ions (Eu3+/Tb3+), ZA through the carbonyl group of MPTMS unit and MOF-253 (or UiO-67) through the double nitrogen of bpydc linker. Subsequently, the obtained multicomponent hybrid materials (ZA-MPTMS-Eu/Tb-MOF-253(UiO-67)) are characterized by means of XRD, FT-IR, SEM and especially the photoluminescence properties are studied in details. These hybrids with both ZA and MOFs host show the main characteristic crystal framework morphology of ZA together with the composition of MOFs. They display the feature luminescence of Eu3+/Tb3+ ions for the energy transfer from bpydc linker of MOFs. Furthermore, ZA-MPTMS-Eu-UiO-67 hybrid material is selected to check the luminescence response to volatile substances, whose luminescence quenching is found for ammonia vapor.

Understanding the structure and role of DNA-PK in NHEJ: How X-ray diffraction and cryo-EM contribute in complementary ways

DNA double-strand breaks (DSBs), generated by ionizing radiation, reactive oxygen species and DNA replication across nicks, are the most severe DNA damage in eukaryotic cells. Non-Homologous End Joining repairs DNA double-strand breaks directly without a template and so can take place at any point in the cell cycle. Ku70/80 heterodimers rapidly assemble around broken DNA ends, allowing DNA-PKcs, the catalytic subunit of DNA-dependent protein kinase, to be recruited and facilitating synapsis of broken DNA ends. This then provides a stage for end-processing and ligation. Here we review progress leading in 2017 to the medium resolution X-ray structure of DNA-PKcs, a single polypeptide chain of 4128 amino acids. This was followed quickly by chain tracing of cryo-EM structures of DNA-PKcs in complex with Ku and DNA. We discuss how combination of structural information from X-ray and cryo-EM studies can produce a working model for complex multicomponent molecular assemblies such as those found in DNA-double-strand-break repair.

Dynamic anticipation by Cdk2/Cyclin A-bound p27 mediates signal integration in cell cycle regulation

p27Kip1 is an intrinsically disordered protein (IDP) that inhibits cyclin-dependent kinase (Cdk)/cyclin complexes (e.g., Cdk2/cyclin A), causing cell cycle arrest. Cell division progresses when stably Cdk2/cyclin A-bound p27 is phosphorylated on one or two structurally occluded tyrosine residues and a distal threonine residue (T187), triggering degradation of p27. Here, using an integrated biophysical approach, we show that Cdk2/cyclin A-bound p27 samples lowly-populated conformations that provide access to the non-receptor tyrosine kinases, BCR-ABL and Src, which phosphorylate Y88 or Y88 and Y74, respectively, thereby promoting intra-assembly phosphorylation (of p27) on distal T187. Even when tightly bound to Cdk2/cyclin A, intrinsic flexibility enables p27 to integrate and process signaling inputs, and generate outputs including altered Cdk2 activity, p27 stability, and, ultimately, cell cycle progression. Intrinsic dynamics within multi-component assemblies may be a general mechanism of signaling by regulatory IDPs, which can be subverted in human disease.

Anion-adaptive crystalline cationic material for 99TcO4\u2212 trapping

Efficient anion recognition is of great significance for radioactive 99TcO4− decontamination, but it remains a challenge for traditional sorbents. Herein, we put forward a tactic using soft crystalline cationic material with anion-adaptive dynamics for 99TcO4− sequestration. A cucurbit[8]uril-based supramolecular metal-organic material is produced through a multi-component assembly strategy and used as a sorbent for effective trapping of TcO4−. Excellent separation of TcO4−/ReO4− is demonstrated by fast removal kinetics, good sorption capacity and high distribution coefficient. Remarkably, the most superior selectivity among metal-organic materials reported so far, together with good hydrolytic stability, indicates potential for efficient TcO4− removal. The structure incorporating ReO4− reveals that the supramolecular framework undergoes adaptive reconstruction facilitating the effective accommodation of TcO4−/ReO4−. The results highlight opportunities for development of soft anion-adaptive sorbents for highly selective anion decontamination.

Soft Materials with Diverse Suprastructures via the Self-Assembly of Metal-Organic Complexes.

Inspired by assemblies in the natural world, researchers have prepared diverse suprastructures with distinct spatial arrangements by artificial self-assembly, including micelles, vesicles, ribbons, films, fibers, and tubes. The field of assembly is undergoing a transition from single-component to multicomponent assembly and single-step to multistep processing. Control over the size, shape, and composition of these building blocks has enabled the formation of suprastructures with substantial structural diversity. More importantly, harnessing noncovalent interactions to create suprastructures in a controlled manner will lead to a better understanding of the formation of complex self-organized patterns. However, for the construction of multiscale self-assemblies with controllable shapes and functions, the selection of a suitable protocol remains challenging. Coordination-driven self-assembly provides a bottom-up approach to construct various metal-organic complexes (MOCs), which could be further used as building blocks with controllable shapes and sizes. Despite the tremendous progress made in the design of MOC-based supramolecular materials, most of these MOCs have dimensions of only several nanometers, and investigations of these structures rely on the characterization of their crystal structure. However, most of the functional suprastructures in living organisms have dimensions ranging from microns to centimeters and have the form of soft materials. Thus, obtaining MOC-based highly ordered materials of larger size remains a challenge. This Account focuses on our recent advances in the construction of soft suprastructure materials with MOCs. A series of functionalized MOCs was first constructed through coordination-driven self-assembly. Then, further self-assembly of the as-prepared MOCs gave rise to the formation of higher-order structures. By changing the functional groups in the acceptors and donors in the MOCs, different suprastructures, including nanospheres, nanodiamonds, nanorods, nanofibers, membranes, films, and gels, were prepared. These studies suggest that using MOCs as building blocks is a highly efficient strategy to achieve complex architectures and functional materials for the development of desired MOC-based soft materials with high precision and fidelity.

Modeling and optimization of multi-component materials selection and sizing problem

Most of the research on materials selection has been characterized by a basic approach to the problem, isolating material choice from the other design variables, and focusing on single components. Instead, a complete approach aimed at optimizing material selection cannot be set aside from component sizing, and the analysis of constraints between components, that characterize the sub-assemblies or the whole system, and can influence the material choice itself. In this paper, a structured method to approach the simultaneous materials selection and sizing optimization of multi-component assemblies is proposed. It is based on a modeling of the problem, fully generalized in its formalization, so as to be applicable to the various cases, and formulated in order to take into account the systemic vision that must have the optimal choice in a multi-component perspective, and its close connection with the sizing of geometric variables, to effectively meet the required performances. In this regard, an efficiency criterion, which provides for the choice of material and variables sizing gauged on real needs, is also introduced. After presenting the framework and formalization of the method, the problem of searching for the best solution has been discussed. With regard to this, a genetic algorithm has been specifically developed according to the peculiarities of the generalized formulation, with the aim of enhancing the heuristic potential of the concurrent material choice and sizing approach in multi-component environment, in the search for the optimal solution. The application to a sub-system of a widely used plant device is reported in detail, so that use and capacity of the structured method are detailed and discussed.

Recent advances towards applications of molecular bottlebrushes and their conjugates

We focus on the most recent developments towards synthesis, modeling, and applications of molecular bottlebrushes. Unique structural characteristics and properties of the bottlebrushes along with an ability to synthetically tailor their structure and functionality open up a number of emergent applications of these polymer systems. The conformation and resulting properties of molecular bottlebrushes and multi-component assemblies encompassing bottlebrushes can be regulated via chemical nature of the backbone and side moieties of bottlebrushes, variation of the distance between grafting points of the side groups, and the degree of polymerization of the side chains. Herein, we highlight the most recent progress in relating the structure of the bottlebrushes with their properties and focus on a number of diverse emerging applications involving bottlebrushes in solvents, melts, and bottlebrushes conjugated with surfaces, interfaces, linear chains, or biomacromolecules. Among such applications are drug delivery and sensing applications, electronic and photonic materials and materials with strain-adaptive stiffening, thermal stabilization and enhancement of activity of enzymes conjugated with copolymer bottlebrushes, and surface modification for biomedical applications.

Formation of multicomponent 2D assemblies of C 2v-symmetric terphenyl tetracarboxylic acid at the solid/liquid interface: recognition, selection, and transformation.

We report on the two-dimensional self-assembly of C2v-symmetric [1,1′:3′,1′′-terphenyl]-3,3′′,5,5′′-tetracarboxylic acid (TPTA) at the solid/liquid interface by using scanning tunneling microscopy (STM). Two kinds of different self-assembly structure, i.e. a close-packed and porous rosette structure, are formed by TPTA molecules through intermolecular hydrogen bonds. When adding coronene (COR) as a guest into the TPTA assembly, structural transformation from a densely packed row structure to a rosette network structure is observed. It was found that two kinds of cavities with different sizes in the rosette network structure can be used to realize the selective co-adsorption of guest molecules with appropriate shape and size. Three-component 2D host–guest structures were successfully constructed by using 1,2,3,4,5,6-hexakis(4-bromophenyl)benzene (HBPBE) and copper phthalocyanine (CuPc) as guest molecules.

Concise synthesis of N-thiomethyl benzoimidazoles through base-promoted sequential multicomponent assembly

An efficient method for the synthesis of N-thiomethyl benzimidazoles from o-phenylenediamines, thiophenols, and aldehydes via C–N/C–S bond formation under metal-free conditions is described. A broad range of functional groups attached to the substrates were well tolerated in this reaction system. Stable and low-toxicity paraformaldehyde was used as the carbon source.

Cobalt‐Zinc‐Diimine Multicatalysis: Enhanced syn Diastereoselectivity in the Reductive Multicomponent Coupling of Aryl Bromides, Acrylates and Aldehydes

AbstractA cobalt‐zinc‐diimine multicatalytic system for the syn‐diastereoselective multicomponent assembly of aromatic bromides, acrylates and aromatic aldehydes under reductive conditions is described. In the presence of catalytic CoBr2phen and the ZnBr2N,N′‐diphenyl cyclohexyldiimine complex, β‐hydroxyesters are obtained with a significant up to 8:1 syn diastereoselectivity whereas reactions conducted without L2‐1 show negligible stereoselectivity. This preliminary study should open the way to further improvements including enantioselective catalysis of the reaction.

Learning to group and label fine-grained shape components

A majority of stock 3D models in modern shape repositories are assembled with many fine-grained components. The main cause of such data form is the component-wise modeling process widely practiced by human modelers. These modeling components thus inherently reflect some function-based shape decomposition the artist had in mind during modeling. On the other hand, modeling components represent an over-segmentation since a functional part is usually modeled as a multi-component assembly. Based on these observations, we advocate that labeled segmentation of stock 3D models should not overlook the modeling components and propose a learning solution to grouping and labeling of the fine-grained components. However, directly characterizing the shape of individual components for the purpose of labeling is unreliable, since they can be arbitrarily tiny and semantically meaningless. We propose to generate part hypotheses from the components based on a hierarchical grouping strategy, and perform labeling on those part groups instead of directly on the components. Part hypotheses are mid-level elements which are more probable to carry semantic information. A multi-scale 3D convolutional neural network is trained to extract context-aware features for the hypotheses. To accomplish a labeled segmentation of the whole shape, we formulate higher-order conditional random fields (CRFs) to infer an optimal label assignment for all components. Extensive experiments demonstrate that our method achieves significantly robust labeling results on raw 3D models from public shape repositories. Our work also contributes the first benchmark for component-wise labeling.

Multicomponent Assembled Systems Based on Platinum(II) Terpyridine Complexes

Platinum(II) terpyridine complexes have received tremendous attention in recent years because of their square-planar geometry and fascinating photophysics. Bottom-up self-assembly represents an intriguing approach to construct well-ordered supramolecular architectures with tunable optical and electronic properties. Until now, much effort has been devoted to the fabrication of monocomponent platinum(II) terpyridine-based assemblies. The next step is to develop multicomponent coassembled systems via the combination of platinum(II) terpyridine complexes with other π-organic and -organometallic molecules. The implementation of electron/energy transfer processes renders advanced functionality to the resulting coassemblies. For the fabrication of discrete multicomponent architectures, a feasible protocol is to construct preorganized molecular tweezers and macrocycles with the involvement of platinum(II) terpyridine complexes as the panel units. In view of their planar surface and positively charged character, such supramolecular receptors are capable of encapsulating electron-rich polyaromatic hydrocarbons and organometallic guests via donor-acceptor charge-transfer and/or metal-metal interactions. Intermolecular hydrogen bonds can be further incorporated between the molecular tweezers receptor and the polyaromatic hydrocarbon guests, giving rise to the strengthened binding affinity and sensitive stimuli-responsiveness. On this basis, multilayer donor-acceptor stacks have been obtained via the precise control over the number of pincers, which feature enhanced complexation strength and superior functionality. Moreover, platinum(II) terpyridine-based macrocycles are more suitable for guest accommodation than the corresponding molecular tweezers receptors in light of their definite size and constrained environment. Stimuli-responsive elements can be conveniently implemented into the rigid spacers of the molecular tweezers and macrocyclic receptors, facilitating the capture and release of the sandwiched guests in a highly controlled manner. On the other hand, long-range-ordered supramolecular polymers have been successfully fabricated with linear, hyperbranched, and cross-linked topologies by employing platinum(II) terpyridine-based molecular tweezers/guest recognition motifs as the non-covalent connecting unit. The degree of polymerization of the resulting donor-acceptor-type supramolecular polymers can be efficiently modulated by incorporating intermolecular hydrogen bonds between the molecular tweezers receptor and the complementary guest unit. An alternative approach toward extended multicomponent donor-acceptor assemblies is to mimic the structure of Magnus' green salt. A delicate balance of non-covalent driving forces between homo- and heterocomplexation processes and a deeper understanding of thermodynamic and kinetic behaviors play the decisive roles in the final arrangement of the coassembled structures. Overall, multicomponent coassembly of platinum(II) terpyridine complexes into well-ordered nanostructures would open up a new avenue toward functional supramolecular materials that are especially promising for sensing, optoelectronics, and catalytic applications.

Bioorthogonal Elastin-like Polypeptide Scaffolds for Immunoassay Enhancement.

Artificial multiprotein complexes are sought after reagents for biomolecular engineering. A current limiting factor is the paucity of molecular scaffolds which allow for site-specific multicomponent assembly. Here, we address this limitation by synthesizing bioorthogonal elastin-like polypeptide (ELP) scaffolds containing periodic noncanonical l-azidohomoalanine amino acids in the guest residue position. The nine azide ELP guest residues served as conjugation sites for site-specific modification with dibenzocyclooctyne (DBCO)-functionalized single-domain antibodies (SdAbs) through strain-promoted alkyne-azide cycloaddition (SPAAC). Sortase A and ybbR tags at the C- and N-termini of the ELP scaffold provided two additional sites for derivatization with small molecules and peptides by Sortase A and 4'-phosphopantetheinyl transferase (Sfp), respectively. These functional groups are chemically bioorthogonal, mutually compatible, and highly efficient, thereby enabling synthesis of multi-antibody ELP complexes in a one-pot reaction. We demonstrate application of this material for enhancing the performance of sandwich immunoassays of the recombinant protein mCherry. In undiluted human plasma, surfaces modified with multi-antibody ELP complexes showed between 2.3- and 14.3-fold improvement in sensitivity and ∼30-40% lower limits of detection as compared with nonspecifically adsorbed antibodies. Dual-labeled multi-antibody ELP complexes were further used for cytometric labeling and analysis of live eukaryotic cells. These results demonstrate how multiple antibodies complexed onto bioorthogonal protein-based polymers can be used to enhance immunospecific binding interactions through multivalency effects.

A Block Supramolecular Polymer and Its Kinetically Enhanced Stability.

Biomolecular systems serve as an inspiration for the creation of multicomponent synthetic supramolecular systems that can be utilized to develop functional materials with complexity. However, supramolecular systems rapidly reach an equilibrium state through dynamic and reversible noncovalent bonds, resulting in a disorganized mixture of components rather than a system in which individual components function cooperatively and/or independently. Thus, efficient synthetic strategies and characterization methods for intricate multicomponent supramolecular assemblies need to be developed. Herein, we report the synthesis of porphyrin-based supramolecular polymers (SPs) in which two distinct block segments consisting of different metal porphyrins are connected: i.e., block supramolecular polymers (BSPs). BSPs with a controlled length and narrow polydispersity were achieved through seeded-growth by a solvent mixing protocol. Interestingly, the block structure permitted the SP as an inner block to coexist with a reagent that was otherwise incompatible with the SP alone. We infer that the inner SP block is compartmentalized in the block structure and endowed with the kinetic stability. Molecular simulations revealed that monomer exchange occurs from the termini of the SP, which corroborated the enhanced stability of the BSP. These results are expected to pave the way for the design of more complex multicomponent supramolecular systems.

High-throughput discovery of organic cages and catenanes using computational screening fused with robotic synthesis

Supramolecular synthesis is a powerful strategy for assembling complex molecules, but to do this by targeted design is challenging. This is because multicomponent assembly reactions have the potential to form a wide variety of products. High-throughput screening can explore a broad synthetic space, but this is inefficient and inelegant when applied blindly. Here we fuse computation with robotic synthesis to create a hybrid discovery workflow for discovering new organic cage molecules, and by extension, other supramolecular systems. A total of 78 precursor combinations were investigated by computation and experiment, leading to 33 cages that were formed cleanly in one-pot syntheses. Comparison of calculations with experimental outcomes across this broad library shows that computation has the power to focus experiments, for example by identifying linkers that are less likely to be reliable for cage formation. Screening also led to the unplanned discovery of a new cage topology—doubly bridged, triply interlocked cage catenanes.

Mechanically Robust Gels Formed from Hydrophobized Cellulose Nanocrystals.

Cellulose nanocrystals (CNCs) that bind to each other through associative hydrophobic interactions have been synthesized by modifying sulfated CNCs (sCNCs) with hydrophobic moieties. These octyl-CNCs form gels at significantly lower concentrations than parent sCNCs, producing extremely strong hydrogels. Unlike sCNCs, these octyl-CNCs do not form ordered liquid crystalline phases indicating a random association into a robust network driven by hydrophobic interactions. Furthermore, involvement of the octyl-CNCs into multicomponent supramolecular assembly was demonstrated in combination with starch. AFM studies confirm favorable interactions between starch and octyl-CNCs, which is thought to be the source of the dramatic increase in gel strength.