High molecular recognition: design of "Keys"

Molecular recognition between molecules is one of the most fundamental processes in biology and chemistry. The recognition process is largely driven by non-covalent forces such as hydrogen bonding, electrostatics, van der Waals forces, pi-pi interactions, and conformational energy. The complementarity between the receptor and substrate is very similar to the "lock and key" function, first described by Emil Fischer over 100 years ago, - the lock being the molecular receptor such as a protein or enzyme and the key being the substrate such as a drug, that is recognized to give a defined receptor-substrate complex. This review focuses on the design of specific ligand systems as "Keys" to enable the induced fit of these keys into the target macromolecules, protein/enzyme (Locks) with particular emphasis on protein recognition.     

Supramolecular functionalization of electron-beam generated nanostructures

Electron-beam lithography was used to pattern poly(styrene-co-(methyldiaminotriazine) styrene) (PS-Triaz). These polymer nanopatterns were utilized as molecular scaffolds for assembling complementary thymine-functionalized CdSe-ZnS quantum dots (Thy-QDs) via three-point hydrogen-bonding molecular recognition. This interaction was very specific, with N-methyl thymine-functionalized QDs (MeThy-QDs) not depositing on the surfaces. The "lock and key" specificity of the assembly is mirrored in the disassembly process, where complete removal of the QD was observed using a competing thymine guest.     

Conformationally imprinted receptors: atropisomers with "write", "save", and "erase" recognition properties

[reaction: see text] An atropisomeric receptor with "write", "save", and "erase" recognition properties is presented. The receptor adopts a complementary conformation when heating in the presence of an ethyl adenine-9-acetate guest molecule. This complementary hydrogen bonding conformation is "saved" upon cooling to room temperature due to the reestablishment of restricted rotation and is stable even upon removal of the guest. Finally, the atropisomeric receptor can be "erased" by heating in the absence of the guest.     

Realization of a "lockable" molecular switch via pH- and redox-modulated cyclization

A switchable organic system involving four distinct states that can be interconverted by use of both pH and redox chemistry as control parameters has been developed. The key molecules involved in this system are the phenanthridine-based heterocycles 1-isobutyl-1,2,3,12b-tetrahydroimidazo[1,2-f]phenanthridine (TIP) and 5-[2-(isobutylamino)ethyl]phenanthridinium (AEP). These two states are interchangeable via pH control, and in addition they can also be further manipulated by oxidation or reduction to convert them to their "pH-inert" forms: 1-isobutyl-2,3-dihydro-1H-imidazo[1,2-f]phenanthridinium (DIP) and 5-[2-(isobutylamino)ethyl]-5,6-dihydrophenanthridine (AEDP), respectively. UV and (1)H NMR experiments carried out in a biphasic dichloromethane (DCM)/water solution were used for in situ structure determination. The results showed that the pH-modulated cyclization and phase-transfer process between the TIP and AEP states was essentially quantitative and repeatable without any significant loss in activity and that reduction or oxidation could be used to lock out these states against such acid-base-induced changes.     

Photoassisted "gate-lock" fluorescence "turn-on" in a new Schiff base and coordination ability of E-Z isomers

Rapid photoresponse (1.0-8.0 min) through fluorescence "turn-on" signaling displayed by a novel Schiff base (L) creating "gate lock" via intramolecular C-H···N interaction in photoisomerized product (L') has been described. Coordination chemistry of pre- and postirradiated species demonstrated a drastic change in the reactivity which has been supported by NMR, HRMS, UV-vis, emission, electrochemical, and complexation studies.     

Specific interactions of complementary mono- and multivalent guests with recognition-induced polymersomes

We have explored the interactions of mono- and multivalent guests with Recognition-Induced Polymersomes (RIPs) formed from complementary random copolymers featuring diamidopyridine and thymine functionality. Addition of monovalent guests featuring imide functionality to these RIPs induced a temporary swelling of the vesicles, followed by dissociation of the vesicles due to competitive binding of the guest. Conversely, multivalent thymine-functionalized nanoparticle guests were rapidly incorporated into the RIPs, inducing a contraction of RIP diameter over time. These mono- and multivalent interactions were extremely specific: highly analogous control systems showed no interaction with the RIP structures. Taken together, these studies demonstrate highly selective molecular "lock and key" control over higher-order assembly and recognition processes.     

Computational analysis of aza analogues of [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranose]-3'-spiro-5"-(4"-amino-1",2"-oxathiole-2",2"-dioxide) (TSAO) as HIV-1 reverse transcriptase inhibitors: relevance of conformational properties on the inhibitory activity

We have carried out a theoretical analysis of aza analogues of [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5"-(4"-amino-1",2"-oxathiole-2",2"-dioxide) by a variety of computational tools, aimed to account for the effect of the endocyclic amino moiety N-2" on the inhibitory activity against HIV-1. Docking studies suggest that compounds substituted at the N-3 and N-2' ' positions present the same binding mode to the [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5"-(4"-amino-1",2"-oxathiole-2",2"-dioxide)thymine prototype, where the endocyclic amino group remains mostly exposed to the solvent. A careful conformational analysis performed through different theoretical levels, from molecular mechanics to high-level quantum mechanical calculations, provides a rationalization based on conformational preferences, which appears as strongly determined by the substitution at N-2", and on electrostatic effects from the bulk water.     

Theoretical investigation of the "CO in"-"CO out" isomerization in a [2Fe-2S] ferredoxin: free energy profiles and redox states

This paper reports on extensive molecular dynamics simulations (about 40 ns in total) in both the reduced and the oxidized states of Ferredoxin from Cyanobacterium Anabaena PCC7119. These calculations have provided us with the free energy profile of the phi(47) backbone angle which controls the "CO in" to "CO out" transition of Cys46 in the reduced and oxidized Fd7119. Our main motivation has been to identify the time scales involved in the reduction of Fd and single out the amino acid residues crucially affecting the conformational change and, thus, electron transfer. The free energy profiles obtained in this study are relevant to electron transfers in the PSI/Fd7119 and Fd7119/FNR complexes. Our findings based on hydrated ferredoxin simulations are that activated processes are to occur in the protein during electron transfer to and from ferredoxin. The relative stability and the activation barrier of the "CO in" to "CO out" transition can be modulated by the distance between the Ser47 and the Glu94 residues. In our calculations, for short distances, the "CO in" state is favored in the reduced form, whereas for large distances, the "CO out" state becomes increasingly favored. Accordingly, conformational changes in Fd7119 when bound to PSI or FNR can have crucial effects on the kinetics of the electron transfer. Our simulations also show that the hydrogen bond between between Ser47(OG) and Cys46(O) is essential to lock in the "CO out" state. This finding explains why only the Ser47Thr Fd7119 mutant sustains electron transfer activity, as only residues serine and threonine can form a specific hydrogen bond with Cys46(O). Finally, our simulations predict that Phe65 has a large probability of being in close contact with the Cys46(O) at the top of the conformational free energy barrier. This carbonyl/phenyl ring interaction can then facilitate the de-localization of the Fd's electron toward the Pi orbitals of Phe65 aromatic ring which is thought to be crucial to the Fd7119/FNR electron transfer     

Fluoride triggered fluorescence "turn on" sensor for Zn2+ ions based on pentaquinone scaffold that works as a molecular keypad lock

A pentaquinone based compound 3a has been synthesized which exhibits pronounced fluorescence enhancement in the presence of Zn(2+) ions under a F(-) triggered synergistic effect. Derivative 3a also behaves as a molecular keypad lock with sequential chemical inputs of Zn(2+) and F(-) ions.     

Fluorescent zinc(II) complex exhibiting "on-off-on" switching toward Cu2+ and Ag+ ions

Binuclear zinc(II) and copper(II) complexes based on a new Schiff base ligand N,N'-bis(2-hydroxybenzilidene)-2,4,6-trimethylbenzene-1,3-diamine (H(2)L) have been synthesized. The ligand H(2)L and complexes under investigation have been characterized by elemental analyses, spectral (FT-IR, (1)H, (13)C NMR, ESI-MS, electronic absorption, emission), and electrochemical studies. The structures of H(2)L and complexes [{Zn(C(23)H(18)N(2)O(2))}(2)] (1) and [{Cu(C(23)H(18)N(2)O(2))}(2)]·H(2)O (2) have been determined crystallographically. Selective "On-Off-On" switching behavior of the fluorescent complex 1 has been studied. The fluorescence intensity of 1 quenches (turns-off) upon addition of Cu(2+), while enhances (turns-on) in the presence of Ag(+) ions. The mechanisms of "On-Off-On" signaling have been supported by (1)H NMR, ESI-MS, electronic absorption, and emission spectral studies. Job's plot analysis supported 1:1 and 1:2 stoichiometries for Cu(2+) and Ag(+) ions, respectively. Association and quenching constants have been estimated by the Benesi-Hildebrand method and Stern-Volmer plot. Moreover, 1 mimics a molecular keypad lock that follows correct chemical input order to give maximum output signal.     

Development of an NMR interface microchip "MICCS" for direct detection of reaction products and intermediates of micro-syntheses using a "MICCS-NMR".

The development of an NMR interface microchip and its applications to the real-time monitoring of chemical reactions are described. The microchip device was named "MICCS" (MIcro Channeled Cell for Synthesis monitoring), and the method using it was named "MICCS-NMR". MICCS was inserted into a 5 mm Phi NMR sample tube. Thus standard solution NMR probes without any modifications can be used in MICCS-NMR measurements. A gap between MICCS and the sample tube was filled with a deuterated solvent for an NMR lock. The reaction temperature and reaction time in MICCS can be easily changed by adjusting the temperature of the NMR probe and changing the flow rates, respectively. The effectiveness of the MICCS-NMR was verified in the real-time monitoring of the Wittig reaction. Preliminary data on the direct detection of intermediates of the Grignard reaction is also reported. Besides real-time monitoring of chemical reactions, MICCS-NMR would be useful as a qualitative detection method for microchip-based synthesis.     

7-N,7'-N'-(1",2"-Dithianyl-3",6"-dimethylenyl)bismitomycin C: synthesis and nucleophilic activation of a dimeric mitomycin

Dimeric alkylating agents that modify complementary DNA strands have engendered significant interest. We have prepared the novel dimeric mitomycin, 7-N,7'-N'-(1",2"-dithianyl-3",6"-dimethylenyl)bismitomycin C (9), in which the mitomycins are bridged by a dithiane unit. Dimer 9, like the clinically tested acyclic disulfides KW-2149 (3) and BMS-181174 (4), was designed to activate under nucleophilic and reductive conditions. Successive nucleophile-mediated disulfide cleavage transformations of 9 are expected to generate thiol species ideally positioned to render the two mitomycin systems vulnerable to nucleophilic attack and permit DNA interstrand cross-link formation. The dithiane linker, strategically positioned between the two mitomycins, distinguished 9 from 3 and 4. Nucleophilic activation of this cyclic disulfide permitted both activated mitomycins to remain tethered to one another. We report the synthesis of 9, and show that the nucleophile Et(3)P markedly enhances the activation and consumption of 9, compared with the reference compound 7-N, 7"-N'-(cyclohexanyl-trans-1",4"-dimethylenyl)bismitomycin C (27). We further demonstrated that provides higher levels of DNA interstrand cross-links than either the dimeric reference compounds, and 7-N,7-N'-(2",5"-dihydroxy-1",6"-hexanediyl)bismitomycin C (28), or the monomeric mitomycins, 1 and 3, when Et(3)P is added to solutions containing EcoRI-linearized pBR322 DNA.     

A molecular keypad lock: a photochemical device capable of authorizing password entries

This paper describes a new concept in the way information can be protected at the molecular scale. By harnessing the principles of molecular Boolean logic, we have designed a molecular device that mimics the operation of an electronic keypad lock, e.g., a common security circuit used for numerous applications, in which access to an object or data is to be restricted to a limited number of persons. What distinguishes this lock from a simple molecular logic gate is the fact that its output signals are dependent not only on the proper combination of the inputs but also on the correct order by which these inputs are introduced. In other words, one needs to know the exact passwords that open this lock. The different password entries are coded by a combination of two chemical and one optical input signals, which can activate, separately, blue or green fluorescence output channels from pyrene or fluorescein fluorophores. The information in each channel is a single-bit light output signal that can be used to authorize a user, to verify authentication of a product, or to initiate a higher process. This development not only opens the way for a new class of molecular decision-making devices but also adds a new dimension of protection to existing defense technologies, such as cryptography and steganography, previously achieved with molecules.     

A Diaminopillar[5]arene-Based Macrobicyclic Molecule: Synthesis,Characterization and A Lock–Key Story

A new macrobicyclic molecule ( BC-DAP5 ), consisting of a diaminopillar[5]arene cavity and a fused ring, was successfully constructed using a Grubbs metathesis reaction. Further studies indicated that BC-DAP5 possessed a unique molecular behavior, showing a response to acid/base stimuli. In BC-DAP5 , protons (acid) acted as a lock, locking the fused ring out of the cavity (pillar[5]arene), and a base served as the key, making the fused ring switch in or out freely. Reversible control of the molecular behavior was achieved simply by adding acid and base alternately.     

Sterically stabilized lock and key colloids: a self-consistent field theory study

A self-consistent field theory study of lock and key type interactions between sterically stabilized colloids in polymer solution is performed. Both the key particle and the lock cavity are assumed to have cylindrical shape and their surfaces are uniformly grafted with polymer chains. The lock-key potential of mean force is computed for various model parameters, such as length of free and grafted chains, lock and key size matching, free chain volume fraction, grafting density, and various enthalpic interactions present in the system. The lock-key interaction is found to be highly tunable, which is important in the rapidly developing field of particle self-assembly.     

Periodic systems of molecules as elements of Shchukarev's "supermatrix", i.e. the chemical element periodic system

Generations of Soviet scientists contributed invaluable insights into molecular classification. Unfortunately, this research is little appreciated in much of the world. Among these workers S. A. Shchukarev was of great importance. His and his followers' legacy includes a host of graphical displays showing enthalpies of formation of gaseous molecules from free atoms DeltaH(a) and standard enthalpies of formation of substances plotted on the atomic number of the central elements, on their oxidation states, their internuclear separations, and other variables for a wide range of molecules. These graphs serve as databases, from which data can be extracted, to moderate precision, visually. We discuss graphs for one very limited set, or "pleiade" (gas-phase oxides of nitrogen), and for three much broader sets, or subsystems (gas-phase fluorides of all main subgroup atoms and oxides of transition-metal atoms in gas-phase and in STP conditions). When dissolved in water, molecules lose their identities but periodicity is echoed in the acids and aquocations that are formed. We show, as an example in tabular form, that redox potentials of high-oxygen acids containing S, Se, and Te change concomitantly with DeltaH(a ) and DeltaH(f) of their hexafluorides. We present graphical evidence that three properties for cations of groups 1-3 (in the short version of the periodic chart) behave similarly and share the periodicity of the elements. One of the properties is related to the ionization potential, which is shown in a tabular example to vary concomitantly with energy of hydration. It was the ultimate goal of S. A. Shchukarev that the transformation of any one graphical database into any other, having different molecules under different conditions, would be made mathematically.     

Total Synthesis of Several 8, 8",-Biflavones

8,8"-Biflavonoidsareantw0rtantclass0fbiflavonoids.Asasystematicresearchofthe8,8"-biflav0noids,wehavepreviouslyreportedthestudyonthereactionof2'-hydroxychaloneswithl2-H2SO4-DMSOsystem.'InthispaPer,thesynthesisof5,5",7,7',-tetTameth0xy-8,8"-biflavonela2,4,4",7,7"-tetramethoxy-8,8"-biflavone1b',4',4",,5,5,',7,7"-hexamethoxy-8,8"-biflav0ne1c4and4,4"-dibenZyl0xy-5,5",7,7"-tetramothoxy-8,8"-biflavoneldisreported.ThesyntheticmethodisshownintheSchemebelow.2-Hydroxyacet0phenonescondensedwithsubsti…     

Fragment occupations in partition Density Functional Theory

The exact ground-state energy and density of a molecule can in principle be obtained via Partition Density Functional Theory (PDFT), a method for calculating molecular properties from Kohn-Sham calculations on isolated fragments. For a given choice of fragmentation, unique fragment densities are found by requiring that the sum of fragment energies be minimized subject to the constraint that the fragment densities sum to the correct molecular ground-state density. We investigate two interrelated aspects of PDFT: the connections between fragment densities obtained via different choices of fragmentation, for which we find "near-additivity", and the nature of their corresponding fragment occupations. Whereas near-integer occupations arise for very large inter-fragment separations, strictly integer occupations appear for small inter-fragment separations. Cases where the fragment chemical potentials cannot be equalized lead to fragment occupations that lock into integers.     

INVESTIGATION OF THE ATRP OF n-BUTYL METHACRYLATE USING THE Cu(I)/N,N,N'''',N",N"-PENTAMETHYLDIETHYLENETRIAMINE CATALYST SYSTEM

INTRODUCTIONThe atom transfer radical polymerization (ATRP) has become an important method for preparing well-definedmacromolecules. This technique offers control over the molecular weights, the chain end functionalities, and thechain architectures[1-12]. It has been used extensively for the preparation of homopolymers, block, and randomcopolymers[13-39], for the preparation of organic/inorganic hybrid materials[40-54], as well as for combining variousother living polymerization methods …     

Romancing the "hidden proteome", Anno Domini two zero zero seven

The mechanism of action and properties of a solid-phase ligand library made of hexapeptides, for capturing the "hidden proteome", i.e. the low- and very low-abundance proteins constituting the vast majority of species in any proteome, be it a cell or tissue lysate or a biological fluid, are here reviewed. Mechanisms of adsorption are evaluated, as well as different protocols for en bloc or sequential elution of the captured polypeptides. Examples are given of capture of proteins from serum, human platelet extracts, bacterial extract and egg white. The increment in detection of low-abundance species appears to be of at least four-fold as compared with untreated samples. One particular aspect of this capture is the adsorption of a high proportion of small peptides (in the Mr 600-8000 Da range) that are normally lost upon electrophoretic two-dimensional mapping. Such a peptide population, in human sera, may be of particular importance since it may contain protein cleavage products of diagnostic value.