Role In Molecular Recognition Research Articles

The Cucurbit[n]uril Family

In 1981, the macrocyclic methylene-bridged glycoluril hexamer (CB[6]) was dubbed "cucurbituril" by Mock and co-workers because of its resemblance to the most prominent member of the cucurbitaceae family of plants--the pumpkin. In the intervening years, the fundamental binding properties of CB[6]-high affinity, highly selective, and constrictive binding interactions--have been delineated by the pioneering work of the research groups of Mock, Kim, and Buschmann, and has led to their applications in waste-water remediation, as artificial enzymes, and as molecular switches. More recently, the cucurbit[n]uril family has grown to include homologues (CB[5]-CB[10]), derivatives, congeners, and analogues whose sizes span and exceed the range available with the alpha-, beta-, and gamma-cyclodextrins. Their shapes, solubility, and chemical functionality may now be tailored by synthetic chemistry to play a central role in molecular recognition, self-assembly, and nanotechnology. This Review focuses on the synthesis, recognition properties, and applications of these unique macrocycles.

Diffusion NMR Spectroscopy in Supramolecular and Combinatorial Chemistry: An Old Parameter — New Insights

AbstractFor Abstract see ChemInform Abstract in Full Text.

Molecular Dynamics Simulation of a High-Affinity Antibody–Protein Complex: The Binding Site is a Mosaic of Locally Flexible and Preorganized Rigid Regions

One nanosecond molecular dynamic (MD) simulation of anti-hen egg white lysozyme (HEL) antibody HyHEL63 (HH63) complexed with HEL reveals rigid and flexible regions of the HH63 binding site. Fifty conformations, extracted from the MD trajectory at regular time intervals were superimposed on HH63-HEL X-ray crystal structure, and the root mean squared deviations (RMSDs) and deviations in Calpha atom positions between the X-ray structure and the MD conformer were measured. Residue positions showing the large deviations in both light chain and heavy chain of the antibody were same in all the MD conformers. The residue positions showing smallest deviations were same for all the conformers in the case of light chain, whereas relatively variable in the heavy chain. Positions of large and small deviations fell in the complementarity determining regions (CDRs), for both heavy and light chains. The larger deviations were in CDR-2 of light and CDR-1 of heavy chain. Smaller deviations were in CDR-3 of light and CDR-2 and CDR-3 of heavy chains. The large and small deviating regions highlight flexible and rigid regions of HH63 binding site and suggest a mosaic binding mechanism, including both "induced fit" and preconfigured "lock-and-key" type of binding. Combined "induced fit" and "lock-and-key" binding would be a better definition for the formation of large complexes, which bury larger surface area on binding, as in the case of antibody-HEL complex. We further show that flexible regions, comprising mostly charged and polar residues, form intermolecular interactions with HEL, whereas rigid regions do not. Electrostatic complementarity between HH63 and HEL also imply optimized binding affinity. Flexible and rigid regions of a high-affinity antibody are selected during the affinity maturation of the antibody and have specific functional significance. The functional importance of local inherently flexible regions is to establish intermolecular contacts or they play a key role in molecular recognition, whereas local rigid regions provide the structural framework.

Dianiline-Diphenol Molecular Complexes Based on Supraminol Recognition

Dianilines and diphenols form well-defined crystalline molecular complexes that arise from complementary O−H···N and N−H···O recognition. The crystal structures of four such 1:1 complexes 1, 2, 3 and 4 based on diphenylmethane frameworks are reported and discussed. Three supramolecular synthons are found, the N(H)O based square motif and infinite chain, already reported, and a new cyclohexane chair consisting of N(H)O, O−H···O and N−H···N hydrogen bridges. The replacement of a −CH2− group by an S-atom leads in two cases to little change in the crystal structure and in another to a complete change. It is possible that the dianiline component plays a more important role in molecular recognition in these complexes than does the diphenol component.

Acyclic Congener of Cucurbituril: Synthesis and Recognition Properties.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Acyclic congener of cucurbituril: synthesis and recognition properties.

The cucurbit[n]uril (CB[n]) family of macrocycles occupies a prominent role in molecular recognition and self-assembly studies despite the current inability to access specific cucurbit[n]uril homologues, derivatives, and analogues by straightforward tailor-made synthetic procedures. In this paper, we explore an approach that circumvents the challenges posed by the tailor-made synthesis of macrocyclic CB[n] by preparing 1, which functions as an acyclic CB[6] congener. The o-xylylene connections to the glycoluril rings preorganize 1 into the (a,a,a,a)-1 conformation required for binding and reduce its tendency to undergo self-association. We surveyed the binding properties of 1 toward 16 amines (K(a) <or= 1.52 x 10(4) M(-)(1)) and diol, diacid, guanidinium, and pyridinium species in pD 7.4 phosphate-buffered D(2)O. We find that the recognition properties of 1 parallel those of CB[6], binding tightly to alkaneammonium species in water and exhibiting length-dependent selectivity and competitive binding with alkali metals present in solution. Compound 1 binds hexanediammonium ion only 180-fold less tightly than CB[6]. The modular synthesis of 1 suggests synthetic methods toward the preparation of acyclic CB[n] congeners with complex functional groups on the edges of their aromatic rings and cavity volumes similar to CB[7] and CB[8]. In combination, these results suggest that acyclic CB[n] congeners hold promise in molecular recognition and self-assembly studies that complements that of macrocyclic CB[n].

Crystal structures of human prostatic acid phosphatase in complex with a phosphate ion and alpha-benzylaminobenzylphosphonic acid update the mechanistic picture and offer new insights into inhibitor design.

The X-ray crystal structure of human prostatic acid phosphatase (PAP) in complex with a phosphate ion has been determined at 2.4 A resolution. This structure offers a snapshot of the final intermediate in the catalytic mechanism and does not support the role of Asp 258 as a proton donor in catalysis. A total of eight hydrogen bonds serve to strongly bind the phosphate ion within the active site. Bound PEG molecules from the crystallization matrix have allowed the identification of a channel within the molecule that likely plays a role in molecular recognition and in macromolecular substrate selectivity. Additionally, the structure of PAP in complex with a phosphate derivative, alpha-benzylaminobenzylphosphonic acid, a potent inhibitor (IC(50) = 4 nM), has been determined to 2.9 A resolution. This structure gives new insight into the determinants of binding hydrophobic ligands within the active site and allows us to explain PAP's preference for aromatic substrates.

DNA recognition by the anthracycline antibiotic respinomycin D: NMR structure of the intercalation complex with d(AGACGTCT)2.

Respinomycin D is a member of the anthracycline family of antitumour antibiotics that interact with double stranded DNA through intercalation. The clinical agents daunomycin and doxorubicin are the most well-studied of this class but have a relatively simple molecular architecture in which the pendant daunosamine sugar resides in the DNA minor groove. Respinomycin D, which belongs to the nogalamycin group of anthracyclines, possesses additional sugar residues at either end of the aglycone chromophore that modulate the biological activity but whose role in molecular recognition is unknown. We report the NMR structure of the respinomycin D-d(AGACGTCT)2 complex in solution derived from NOE restraints and molecular dynamics simulations. We show that the drug threads through the DNA double helix forming stabilising interactions in both the major and minor groove, the latter through a different binding geometry to that previously reported. The bicycloaminoglucose sugar resides in the major groove and makes specific contacts with guanine at the 5'-CpG intercalation site, however, the disaccharide attached at the C4 position plays little part in drug binding and DNA recognition and is largely solvent exposed.

Electrostatic Analysis and Brownian Dynamics Simulation of the Association of Plastocyanin and Cytochrome F

The oxidation of cytochrome f by the soluble cupredoxin plastocyanin is a central reaction in the photosynthetic electron transfer chain of all oxygenic organisms. Here, two different computational approaches are used to gain new insights into the role of molecular recognition and protein-protein association processes in this redox reaction. First, a comparative analysis of the computed molecular electrostatic potentials of seven single and multiple point mutants of spinach plastocyanin (D42N, E43K, E43N, E43Q/D44N, E59K/E60Q, E59K/E60Q/E43N, Q88E) and the wt protein was carried out. The experimentally determined relative rates ( k 2) for the set of plastocyanin mutants are found to correlate well ( r 2 = 0.90 − 0.97) with the computed measure of the similarity of the plastocyanin electrostatic potentials. Second, the effects on the plastocyanin/cytochrome f association rate of these mutations in the plastocyanin “eastern site” were evaluated by simulating the association of the wild type and mutant plastocyanins with cytochrome f by Brownian dynamics. Good agreement between the computed and experimental relative rates ( k 2) ( r 2 = 0.89 − 0.92) was achieved for the plastocyanin mutants. The results obtained by applying both computational techniques provide support for the fundamental role of the acidic residues at the plastocyanin eastern site in the association with cytochrome f and in the overall electron-transfer process.

Metal Ion-Assisted Weak Interactions Involving Biological Molecules. From Small Complexes to Metalloproteins

Abstract Noncovalent or weak interactions play important roles in molecular recognition and structual organization in chemical and biological systems. Hydrogen bonding and aromatic ring stacking are widely recognized for biomolecules, and these and other types of weak interactions are recently attracting much attention as a clue to understanding the efficiency and specificity of biological reactions. We studied weak interactions around the metal center as factors for mixed ligand (ternary) metal complex formation, molecular recognition, and construction of self-organized structures by potentiometric, spectroscopic, and crystallographic methods. We concluded the electrostatic ligand–ligand interactions within Cu(II) and Pd(II) complexes containing an acidic and a basic amino acid and aromatic ring stacking interactions between the aromatic rings of an aromatic amino acid and a coordinated aromatic ligand such as 2,2′-bipyridine. Selective adduct formation between Pt(II) complexes and uncoordinated mononucleotides were found to occur through stacking and hydrogen bonding. In the systems with aromatic ring stacking, a close metal–aromatic ring contact was revealed in the solid state, and the 195Pt NMR spectra indicated electron density decrease due to stacking. As an extension of such studies, we investigated metalloprotein–charged peptide electrostatic interactions and established the redox partner binding site of plastocyanin and its subtle structural change due to the interactions. The results demonstrated the use of charged oligopeptides as models for the studies on protein–protein binding. Weak interactions between [Cu(arginine)2]2+ and its counterions, such as benzene-1,3-dicarboxylate, led to controlled self-organization of the complex ion, giving crystalline products with handed single-helical or double-helical structures and layer structures, depending on the anions used.

Weak interactions and molecular recognition in systems involving electron transfer proteins

Electrostatic interactions and other weak interactions between amino acid side chains on protein surfaces play important roles in molecular recognition, and the mechanism of their intermolecular interactions has gained much interest. We established that charged peptides are useful for investigating the molecular recognition character of proteins and their molecular interaction induced structural changes. Positively charged lysine peptides competitively inhibited electron transfer from reduced cytochrome f (cyt f or cytochrome c (cyt c) to oxidized plastocyanin (PC), due to neutralization of the negatively charged site of PC by formation of PC-lysine peptide complexes. Lysine peptides also inhibited electron transfer from cyt c to cytochrome c peroxidase. Likewise, negatively charged aspartic acid peptides interacted with the positively charged sites of cytfand cyt c, and competitively inhibited electron transfer from reduced cytfor cyt c to oxidized PC and from [Fe(CN)6]4- to oxidized cyt c. Changes in the geometry and a shift to a higher redox potential of the active site Cu of PC on oligolysine binding were detected by spectroscopic and electrochemical measurements, owing to the absence of absorption in the visible region for lysine peptides. Structural and redox potential changes were also observed for cyt f and cyt c by interaction with aspartic acid peptides.

The role of molecular recognition in charge transport properties of doped polyaniline.

Molecular recognition plays a significant role in the counterion-induced processibility, morphological features, and physical properties of doped polyaniline (PANI). The interaction of the counterion and solvent controls the chain conformation and, as a result, the formation of extended and localized electronic states; hence, it holds the key for tuning a wide range of electrical and optical properties of doped PANI. The combined effects of counterion, solvent, and processing conditions tune the metal-insulator transition, temperature dependence of conductivity, magnetoresistance, and so forth in doped PANI. The typical examples are shown in the case of PANI doped by camphor sulfonic acid, 2-acrylamido-2-methyl-1-propane sulfonic acid, and dodecylbenzoyl sulfonic acid.

Cation−π Interactions in Proteins: Can Simple Models Provide an Accurate Description?

It has been suggested that cation−π interactions constitute a strong, specific driving force that plays a key role in molecular recognition. The importance of such interactions in biological systems is explored here via two complementary approaches. The first one relies on an analysis of the association of phenylalanine, tyrosine, and tryptophan with arginine and lysine in 1718 representative protein structures, highlighting orientational preferences in cation−π complexes. The second one consists of an MP2/6-311++G**//MP2/6-31G** ab initio investigation of the dimers formed by relevant models of the amino acid side chains that are engaged in cation−π interactions. The estimated induction contribution to the binding energies confirms that polarization effects are significant. The ability of commercial, two-body potential energy functions to describe cation−π interactions accurately is also investigated, and the inclusion of correcting parameters in the force field is discussed. Put together, these results provide new insights into the nature of cation−π association in proteins.

Molecular Recognition and Interfacial Catalysis at Liquid-Liquid Interfaces

The interface between two immiscible liquids with immobilized metalloporphyrins, enzymes and submitochondrial particles can serve as the simplest model of biological membrane convenient for the investigation of redox reaction accompanied by spatial separation of charges. In this mini review, we have described the vectorial charge transfer and molecular recognition at liquid/liquid interfaces. The structure of liquid interfaces, donor-acceptor interactions in the electrical double layer, hydrogen and specific bounding between molecules play the dominant role in molecular recognition and interfacial catalysis.

Conformational studies of paclitaxel analogs modified at the C-2' position in hydrophobic and hydrophilic solvent systems.

The conformations of two paclitaxel analogs modified at the C-2' position, 2'-deoxypaclitaxel and 2'-methoxypaclitaxel, were studied in hydrophobic and hydrophilic solvent systems by a combination of NMR spectroscopy, CD measurements, and molecular modeling. Both analogs have hydrophobic and hydrophilic conformations that resemble those of paclitaxel itself in the same media. Since the two have diminished biological activities in a number of bioactivity assays and the hydrogen-bonding capability of the 2'-hydroxyl group has been eliminated, we postulate that this group is involved in hydrogen bonding with tubulin and plays an important role in molecular recognition. The results of this study are in agreement with our earlier report on paclitaxel 2'-acetate, an analog in which the 2'-hydroxyl group hydrogen-bonding capacity has also been eliminated.

有機合成化学の挑戦‐２１世紀に向けて 生体機能関連 人工超分子：多点相互作用の展開

Multiple interaction plays important roles in molecular recognition. In the present article are described recent advances in the supramolecular multiple interactions. It is composed of three parts. The first one deals with a strategic switch from convergent multiple interaction sites to divergent ones. The latter is suited not for host-guest complexation but for intermolecular network formation and hence allows molecular alignment control in crystals. In the second part is shown the use of templates to induce biologically-significant supramolecular structures such as α-helical folding of peptides and sugar clusters. The last part is concerned with how multiple hydrogen bonding interaction can become effective in aqueous media. Examples include a membrane-forming cooperation of hydrogen bonding and hydrophobic effect, a very strong adsorption of a macrocyclic sugar cluster on polar solid surfaces, and guest-binding supramolecular cavities in microporous crystals maintained by hydrogen-bonds.

Molecular recognition applied to sensors

The role of molecular recognition by synthetic receptor molecules in the signal generation of CHEMFET sensors is discussed together with their self-organization on gold surfaces.

Molecular recognition in biological systems: from activation to inhibition.

A fine-tuned system of molecular recognition is a fundamental feature of all biological processes. Although the basic principles of how molecular surfaces fit together in a complementary fashion have been established to a first approximation, the details of the interplay between electrostatic, steric, entropic and solvation effects are not well understood. To provide insight into the stereochemical factors that govern recognition and packing at protein interfaces, a host of biochemical and biophysical techniques have been applied. Perhaps the most widely used of these techniques are mutagenesis and crystallography, and when used together they have proved to be extremely powerful in defining the functional elements that are important in protein interactions. Using these protein-engineering techniques we have focused our studies on the role of molecular recognition in two important, but distinctly different, biological processes: ( 1) the role of molecular recognition in receptor activation, and (2) the stereochemical factors that define specificity and provide binding energy to inhibitors that are associated with their target proteinases. Our findings, discussed below, suggest that the conventional wisdom about specificity and binding needs to be rethought.

Atomic structures and function of periplasmic receptors for active transport and chemotaxis

Well refined very-high-resolution structures of seven receptors that serve as primary components of bacterial active transport have provided a detailed new understanding of the atomic interactions associated with the specific recognition and binding of a variety of substances such as sulfate, phosphate, leucine, monosaccharides and oligosaccharides. Irrespective of the nature of the ligands, hydrogen bonds play a key and dominant role in molecular recognition and interactions. It is notable that no salt linkages, counterions or water molecules are associated with the bound charged ligands. These findings have important ramifications in several biological processes, notably active transport, rapid ion movement, and enzyme catalysis.

Mapping the binding sites of human erythrocyte ankyrin for the anion exchanger and spectrin.

This report describes initial characterization of the binding sites of ankyrin for spectrin and the anion exchanger using defined subfragments isolated from purified ankyrin domains. The spectrin-binding domain of ankyrin is comprised of two subdomains: an acidic, proline-rich region (pI = 4) involving the amino-terminal 80 residues from 828 to 908 and a basic region (pI = 8.8) that extends from 898 to 1386. The amino-terminal 70 amino acids of the spectrin-binding domain are critical for association with spectrin, since a subfragment missing this region is only 5% as active as the intact domain in displacing binding of spectrin to inside-out membrane vesicles, while deletion of the first 38 residues of the acidic domain results in a 10-fold reduction in activity. The anion exchanger-binding site is confined to an 89-kDa domain that was isolated and characterized as a globular molecule with approximately 30% alpha-helical configuration. A subfragment of the 89-kDa domain extending from residues 403 to 779 (or possibly 740) retains ability to associate with the anion exchanger. The 89-kDa domain is comprised of a series of tandem repeats of 33 amino acids that extend from residues 35 to 778 (Lux, S., John, K., and Bennett, V. (1990) Nature 344, 36-42). The activity of residues 403-779 demonstrates that the 33-amino acid repeats of the 89-kDa domain are responsible for association between ankyrin and the anion exchanger. The 33-amino acid repeating sequence of ankyrin represents an ancient motif also found in proteins of Drosophila, yeast, and Caenor habditis elegans. The finding that the 33-amino acid repeating sequence is involved in interaction with the anion exchanger implies that this motif may perform a role in molecular recognition in diverse proteins.