Chemical strategies and characterization tools for the organization of single molecule magnets on surfaces

Addressing individual bistable magnetic molecules, known as Single Molecule Magnets (SMMs), is a fascinating goal at the borderline between molecular magnetism and spin electronics. This tutorial review focuses on the first step towards single-molecule experiments, namely the organization of SMMs on surfaces. Both preparation and characterization of surface-supported SMMs prove to be quite demanding and a multidisciplinary approach is necessary, which is described here using selected examples. We first illustrate the chemical strategies devised to assemble SMMs and to control their orientation on surfaces. Then, we present characterization tools, which have been selected on the basis of their relevance to address specific points, i.e. the chemical composition of the deposited SMM films, the organization of the molecules on the surface, the intramolecular arrangement of the spins, the magnetic anisotropy of SMMs, and eventually the dynamics of their magnetization on surfaces. Particular attention is devoted to techniques exploiting synchrotron light.     

Design-atom approach for the quantum mechanical/molecular mechanical covalent boundary: a design-carbon atom with five valence electrons

A critical issue underlying the accuracy and applicability of the combined quantum mechanical/molecular mechanical (QM/MM) methods is how to describe the QM/MM boundary across covalent bonds. Inspired by the ab initio pseudopotential theory, here we introduce a novel design atom approach for a more fundamental and transparent treatment of this QM/MM covalent boundary problem. The main idea is to replace the boundary atom of the active part with a design atom, which has a different number of valence electrons but very similar atomic properties. By modifying the Troullier-Martins scheme, which has been widely employed to construct norm-conserving pseudopotentials for density functional calculations, we have successfully developed a design-carbon atom with five valence electrons. Tests on a series of molecules yield very good structural and energetic results and indicate its transferability in describing a variety of chemical bonds, including double and triple bonds.     

IADE: a system for intelligent automatic design of bioisosteric analogs

IADE, a software system supporting molecular modellers through the automatic design of non-classical bioisosteric analogs, scaffold hopping and fragment growing, is presented. The program combines sophisticated cheminformatics functionalities for constructing novel analogs and filtering them based on their drug-likeness and synthetic accessibility using automatic structure-based design capabilities: the best candidates are selected according to their similarity to the template ligand and to their interactions with the protein binding site. IADE works in an iterative manner, improving the fitness of designed molecules in every generation until structures with optimal properties are identified. The program frees molecular modellers from routine, repetitive tasks, allowing them to focus on analysis and evaluation of the automatically designed analogs, considerably enhancing their work efficiency as well as the area of chemical space that can be covered. The performance of IADE is illustrated through a case study of the design of a nonclassical bioisosteric analog of a farnesyltransferase inhibitor??an analog that has won a recent ??Design a Molecule?? competition.     

Opening the Pandora's jar of molecule‐to‐material conversion in chemical vapor deposition: Insights from theory

First‐principles modeling can be a powerful tool for the understanding and optimization of bottom‐up processes for nanomaterials fabrication, such as chemical vapor deposition (CVD), a key technology for the development of advanced systems and devices. Molecule‐to‐material conversion by CVD involves complex chemical phenomena, which are often obscure and still largely unexplored. A proper modeling would require high level of accuracy, large sized models and should include both temperature effects and statistical sampling of reactive events. By presenting a few selected examples, this perspective surveys such problems and discusses currently available approaches for their solution. Possible strategies for future advances in the field are also highlighted. © 2013 Wiley Periodicals, Inc.     

应用前沿亲和色谱研究分子之间相互作用及其应用

分子间的相互作用是一切生物或化学变化的基础。前沿亲和色谱作为通用性的研究分子间相互作用力的工具,利用它可得到分子之间相应的解吸常数K_d,并可对各种配体的亲和力大小进行排序。本文介绍了前沿亲和色谱的工作原理、前沿亲和色谱柱的构建,以及在药物筛选,生物相关领域的应用。与其他研究分子间相互作用的技术作了相应的比较。     

Experimental/theoretical electrostatic properties of a styrylquinoline-type HIV-1 integrase inhibitor and its progenitors

We have established that polyhydroxylated styrylquinolines are potent inhibitors of HIV-1 integrase (IN). Among them, we have identified (E)-8-hydroxy-2-[2-(4,5-dihydroxy-3-methoxyphenyl)-ethenyl]-7-quinolinecarboxylic acid (1) as a promising lead. Previous molecular dynamics simulations and docking procedures have shown that the inhibitory activity involves one or two metal cations (Mg2+), which are present in the vicinity of the active center of the enzyme. However, such methods are generally based on a force-field approach and still remain not as reliable as ab initio calculations with extended basis sets on the whole system. To go further in this area, the aim of the present study was to evaluate the predictive ability of the electron density and electrostatic properties in the structure-activity relationships of this class of HIV-1 antiviral drugs. The electron properties of the two chemical progenitors of 1 were derived from both high-resolution X-ray diffraction experiments and ab initio calculations. The twinning phenomenon and solvent disorder were observed during the crystal structure determination of 1. Molecule 1 exhibits a planar s-trans conformation, and a zwitterionic form in the crystalline state is obtained. This geometry was used for ab initio calculations, which were performed to characterize the electronic properties of 1. The electron densities, electrostatic potentials, and atomic charges of 1 and its progenitors are here compared and analyzed. The experimental and theoretical deformation density bond peaks are very comparable for the two progenitors. However, the experimental electrostatic potential is strongly affected by the crystal field and cannot straightforwardly be used as a predictive index. The weak difference in the theoretical electron densities between 1 and its progenitors reveals that each component of 1 conserves its intrinsic properties, an assumption reinforced by a 13C NMR study. This is also shown through an excellent correlation of the atomic charges for the common fragments. The electrostatic potential minima in zwitterionic and nonzwitterionic forms of 1 are discussed in relation with the localization of possible metal chelation sites.     

Universal peptidomimetics

This paper concerns peptidomimetic scaffolds that can present side chains in conformations resembling those of amino acids in secondary structures without incurring excessive entropic or enthalpic penalties. Compounds of this type are referred to here as minimalist mimics. The core hypothesis of this paper is that small sets of such scaffolds can be designed to analogue local pairs of amino acids (including noncontiguous ones) in any secondary structure; i.e., they are universal peptidomimetics. To illustrate this concept, we designed a set of four peptidomimetic scaffolds. Libraries based on them were made bearing side chains corresponding to many of the protein-derived amino acids. Modeling experiments were performed to give an indication of kinetic and thermodynamic accessibilities of conformations that can mimic secondary structures. Together, peptidomimetics based on these four scaffolds can adopt conformations that resemble almost any combination of local amino acid side chains in any secondary structure. Universal peptidomimetics of this kind are likely to be most useful in the design of libraries for high-throughput screening against diverse targets. Consequently, data arising from submission of these molecules to the NIH Molecular Libraries Small Molecule Repository (MLSMR) are outlined.     

Specific Versus Non-specific Response in Exponential Molecular Amplification from Cross-Catalysis: Modeling the Influence of Background Amplifications on the Analytical Performances

Molecule based signal amplifications relying on an autocatalytic process may represent an ideal strategy for the development of ultrasensitive analytical or bioanalytical assays, the main reason being the exponential nature of the amplification. However, to take full advantage of such amplification rates, high stability of the starting co-reactants is required in order to avoid any undesirable background amplification. Here, on the basis of a simple kinetic model of cross-catalysis including a certain degree of intrinsic instability of co-reactants, we highlight the key parameters governing the analytical response of the system and discuss the analytical performances that are expected from a given kinetic set. In particular, we show how the detection limit is directly related to the relative instability of reactants within each catalytic loop. The model is validated with an experimental dataset and is intended to serve as a guide in the design and optimization of autocatalytic molecular-based amplification systems with improved analytical performances.     

Second-Generation Covalent TMP-Tag for Live Cell Imaging

Chemical tags are now viable alternatives to fluorescent proteins for labeling proteins in living cells with organic fluorophores that have improved brightness and other specialized properties. Recently, we successfully rendered our TMP-tag covalent with a proximity-induced reaction between the protein tag and the ligand-fluorophore label. This initial design, however, suffered from slow in vitro labeling kinetics and limited live cell protein labeling. Thus, here we report a second-generation covalent TMP-tag that has a fast labeling half-life and can readily label a variety of intracellular proteins in living cells. Specifically, we designed an acrylamide-trimethoprim-fluorophore (A-TMP-fluorophore v2.0) electrophile with an optimized linker for fast reaction with a cysteine (Cys) nucleophile engineered just outside the TMP-binding pocket of Escherichia coli dihydrofolate reductase (eDHFR) and developed an efficient chemical synthesis for routine production of a variety of A-TMP-probe v2.0 labels. We then screened a panel of eDHFR:Cys variants and identified eDHFR:L28C as having an 8-min half-life for reaction with A-TMP-biotin v2.0 in vitro. Finally, we demonstrated live cell imaging of various cellular protein targets with A-TMP-fluorescein, A-TMP-Dapoxyl, and A-TMP-Atto655. With its robustness, this second-generation covalent TMP-tag adds to the limited number of chemical tags that can be used to covalently label intracellular proteins efficiently in living cells. Moreover, the success of this second-generation design further validates proximity-induced reactivity and organic chemistry as tools not only for chemical tag engineering but also more broadly for synthetic biology.     

Chemical measurement and data reduction from a systems analysis perspective

Low-cost, high-performance computation is now available with many analytical instruments. Data reduction methods now employed use relatively little of the information and the computing power available from these instruments. An alternative way of analyzing chemical measurement data involves the use of concepts from system theory. System theory was developed to analyze time series data produced by very complicated processes. It is proposed here that systems analysis methods have a number of applications in the reduction of chemical data. Full use of these methods may change the way in which chemical data are collected as well.     

Design and dynamic characterization of "single-stroke" peristaltic PDMS micropumps

In this paper, we present a monolithic PDMS micropump that generates peristaltic flow using a single control channel that actuates a group of different-sized microvalves. An elastomeric microvalve design with a raised seat, which improves bonding reliability, is incorporated into the micropump. Pump performance is evaluated based on several design parameters--size, number, and connection of successive microvalves along with control channel pressure at various operating frequencies. Flow rates ranging 0-5.87 μL min(-1) were observed. The micropump design demonstrated here represents a substantial reduction in the number of/real estate taken up by the control lines that are required to run a peristaltic pump, hence it should become a widespread tool for parallel fluid processing in high-throughput microfluidics.     

Versatile low-molecular-weight hydrogelators: achieving multiresponsiveness through a modular design

Multiresponsive low-molecular-weight hydrogelators (LMWHs) are ideal candidates for the development of smart, soft, nanotechnology materials. The synthesis is however very challenging. On the one hand, de novo design is hampered by our limited ability to predict the assembly of small molecules in water. On the other hand, modification of pre-existing LMWHs is limited by the number of different stimuli-sensitive chemical moieties that can be introduced into a small molecule without seriously disrupting the ability to gelate water. Herein we report the synthesis and characterization of multistimuli LMWHs, based on a modular design, composed of a hydrophobic, disulfide, aromatic moiety, a maleimide linker, and a hydrophilic section based on an amino acid, here N-acetyl-L-cysteine (NAC). As most LMWHs, these gelators experience reversible gel-to-sol transition following temperature changes. Additionally, the NAC moiety allows reversible control of the assembly of the gel by pH changes. The reduction of the aromatic disulfide triggers a gel-to-sol transition that, depending on the design of the particular LMWH, can be reverted by reoxidation of the resulting thiol. Finally, the hydrolysis of the cyclic imide moieties provides an additional trigger for the gel-to-sol transition with a timescale that is appropriate for use in drug-delivery applications. The efficient response to the multiple external stimuli, coupled to the modular design makes these LMWHs an excellent starting point for the development of smart nanomaterials with applications that include controlled drug release. These hydrogelators, which were discovered by serendipity rather than design, suggest nonetheless a general strategy for the introduction of multiple stimuli-sensitive chemical moieties, to offset the introduction of hydrophilic moieties with additional hydrophobic ones, in order to minimize the upsetting of the critical hydrophobic-hydrophilic balance of the LMWH.     

Some basic data structures and algorithms for chemical generic programming

Here, we report a template library used for molecular operation, the Molecular Handling Template Library (MHTL). The library includes some generic data structures and generic algorithms, and the two parts are associated with each other by two concepts: Properties and Molecule. The concept Properties describes the interface to access objects' properties, and the concept Molecule describes the minimum requirement for a molecular class. Data structures include seven models of Properties, each using a different method to access properties, and two models of molecular classes. Algorithms include molecular file manipulation subroutines, SMARTS language interpreter and matcher functions, and molecular OpenGL rendering functions.     

Structure-based design and combinatorial chemistry yield low nanomolar inhibitors of cathepsin D

Background: The identification of potent small molecule ligands to receptors and enzymes is one of the major goals of chemical and biological research. Two powerful new tools that can be used in these efforts are combinatorial chemistry and structure-based design. Here we address how to join these methods in a design protocol that produces libraries of compounds that are directed against specific macromolecular targets. The aspartyl class of proteases, which is involved in numerous biological processes, was chosen to demonstrate this effective procedure.Results: Using cathepsin D, a prototypical aspartyl protease, a number of low nanomolar inhibitors were rapidly identified. Although cathepsin D is implicated in a number of therapeutically relevant processes, potent nonpeptide inhibitors have not been reported previously. The libraries, synthesized on solid support, displayed nonpeptide functionality about the (hydroxyethyl)amine isostere. The (hydroxyethyl)amine isostere, which targets the aspartyl protease class, is a stable mimetic of the tetrahedral intermediate of amide hydrolysis. Structure-based design, using the crystal structure of cathepsin D complexed with the peptide-based natural product pepstatin, was used to select the building blocks for the library synthesis. The library yielded a ‘hit rate’ of 6–7% at 1 μM inhibitor concentrations, with the most potent compound having a K_i value of 73 nM. More potent, nonpeptide inhibitors (K_i = 9–15 nM) of cathepsin D were rapidly identified by synthesizing and screening a small second generation library.Conclusions: The success of these studies clearly demonstrates the power of coupling the complementary methods of combinatorial chemistry and structure-based design. We anticipate that the general approaches described here will be successful for other members of the aspartyl protease class and for many other enzyme classes.     

The thermal stability of fully charged and discharged LiCoO2 cathode and graphite anode in nitrogen and air atmospheres

Polyethylene glycol (PEG) compounds and mixtures have many properties that make them suitable for thermal applications in buildings, such as having high heat of fusion, phase change repeatability, chemical stability, non-corrosive behavior, and low-cost. In this study, we developed a number of PU rigid foams incorporated with three types of PEGs, as new insulation materials provided with an enhanced thermal capacity, and sought their suitability for various applications such as layer of floor and ceiling coverings in constructions, insulations in controlled temperature transportation packaging, inner coverings of automobile seats, etc. In order to investigate the thermal properties of PEG-containing PU foams, differential scanning calorimeter (DSC) tests were conducted first. Then, a two-layer concrete–PU foam system was designed in the laboratory conditions to examine the insulation performances via using a computer-aided thermal measurement setup which was sensitive to the simulated environmental temperature changes. The PU-PEG composites produced here can be helpful for the design of thermal insulators. PUI, including 44% PEG 600, exhibited fairly efficient thermal regulation under moderate ambient temperature conditions, whereas PUII (49% PEG 1000) is suitable for temperature control in both mild and hot surroundings. PUIII, containing 53% PEG 1500, showed suitable heat storage and thermal stability characteristics. PUIV, containing 38% PEG 600/PEG 1000/PEG 1500, also confirmed good thermal and durability characteristics. The blend of three PEGs is suitable for preventing discontinuous thermal regulation when the external temperature increases or decreases. PU foams containing PEGs can be assumed to be leak-resistant, which is promising for their industrial applications.     

Rational principles of compound selection for combinatorial library design

It is practically impossible in a short period of time to synthesize and test all compounds in any large exhaustive chemical library. We discuss rational approaches to selecting representative subsets of virtual libraries that help direct experimental synthetic efforts for both targeted and diverse library design. For targeted library design, we consider principles based on the similarity to lead molecules. In the case of diverse library design, we discuss algorithms aimed at the selection of both diverse and representative subsets of the entire chemical library space. We illustrate methodologies with several practical examples.     

Enabling drug discovery project decisions with integrated computational chemistry and informatics

Computational chemistry/informatics scientists and software engineers in Genentech Small Molecule Drug Discovery collaborate with experimental scientists in a therapeutic project-centric environment. Our mission is to enable and improve pre-clinical drug discovery design and decisions. Our goal is to deliver timely data, analysis, and modeling to our therapeutic project teams using best-in-class software tools. We describe our strategy, the organization of our group, and our approaches to reach this goal. We conclude with a summary of the interdisciplinary skills required for computational scientists and recommendations for their training.     

Synthesis and properties of a blue bipolar indenofluorene emitter based on a D-π-A design

Through a rational design, a novel Donor-Acceptor π-conjugated (D-π-A) blue fluorescent indenofluorene dye, DA-DSF-IF, has been synthesized for application in single-layer Small Molecule Organic Light Emitting Diodes (SMOLEDs). This new blue emitter possesses bipolar properties as well as good morphological and emission color stabilities and has been successfully used in a blue emitting single-layer SMOLED, with performances impressively magnified compared to a nonbipolar indenofluorene emitter.     

Thermal growth of organic supramolecular crystals with screw dislocations

We report here a simple pathway to thermally assemble acene-based molecules into large crystals without modification of their chemical structures. Differential scanning calorimetry was used to characterize properly thermal events occurring during successive heating and cooling processes. More interestingly, observations by means of polarized light microscopy (POM) revealed that a spontaneous formation of screw dislocations within crystals during the isothermal treatment triggered a structural reorganization by forming large and well-defined spiral architectures. After this reorganization, new crystals showed an excellent ordering in both vertical and horizontal directions. Due to the richness in pi-electrons of acene-based molecules, we expect this work of importance to organic electronics, especially in the design of new molecular building blocks and investigation of their assembly into sophisticated supramolecular structures.