Principles Of Molecular Recognition Research Articles

Facilitated transport of organics of biological interest: I. A new alternative for the separation of amino acids by fixed-site crown-ether polysiloxane membranes

Fixed-site heteropolysiloxane membranes containing grafted macrocyclic receptors can separate a mixture of amino acids. These membranes have an intermediate configuration between liquid membranes (selective complexation by a specific carrier) and solid membranes (charge interactions). The solution–diffusion model, which was used to analyze experimental transport results for these membranes, provided evidence for a new dual transport mechanisms. With an acidic pH of the feed phase, the selectivity of the transport (symport of protons) relative to l-α-alanine (Ala) was high and dependent on the relative hydrophobicity of the amino acids ( l-phenylaniline (Phe), leucine (Leu)) ( S=7–10), whereas no selectivity was obtained when the pH of the feed phase was higher. The proton-driven transport increased the flux and caused the transport rates of amino acids to be widely spread out due to different molecular recognition principles effecting transport. An active transport mechanism of amino acids is possibly present in the solid dense polymeric matrix.

Programming the assembly of two- and three-dimensional architectures with DNA and nanoscale inorganic building blocks.

The use of biochemical molecular recognition principles for the assembly of nanoscale inorganic building blocks into macroscopic functional materials constitutes a new frontier in science. This article details efforts pertaining to the use of sequence-specific DNA hybridization events and novel inorganic surface coordination chemistry to control the formation of both two- and three-dimensional functional architectures.

Recent developments in structure-based drug design.

Structure-based design has emerged as a new tool in medicinal chemistry. A prerequisite for this new approach is an understanding of the principles of molecular recognition in protein-ligand complexes. If the three-dimensional structure of a given protein is known, this information can be directly exploited for the retrieval and design of new ligands. Structure-based ligand design is an iterative approach. First of all, it requires the crystal structure or a model derived from the crystal structure of a closely related homolog of the target protein, preferentially complexed with a ligand. This complex unravels the binding mode and conformation of a ligand under investigation and indicates the essential aspects determining its binding affinity. It is then used to generate new ideas about ways of improving an existing ligand or of developing new alternative bonding skeletons. Computational methods supplemented by molecular graphics are applied to assist this step of hypothesis generation. The features of the protein binding pocket can be translated into queries used for virtual computer screening of large compound libraries or to design novel ligands de novo. These initial proposals must be confirmed experimentally. Subsequently they are optimized toward higher affinity and better selectivity. The latter aspect is of utmost importance in defining and controlling the pharmacological profile of a ligand. A prerequisite to tailoring selectivity by rational design is a detailed understanding of molecular parameters determining selectivity. Taking examples from current drug development programs (HIV proteinase, t-RNA transglycosylase, thymidylate synthase, thrombin and, related serine proteinases), we describe recent advances in lead discovery via computer screening, iterative design, and understanding of selectivity discrimination.

Oligonucleotide aptamers that recognize small molecules

Nucleic acid receptors ('aptamers'), which recognize a large variety of organic molecules of low molecular weight, have been isolated from combinatorial nucleic acid libraries by in vitro selection methods. Structural studies of nucleic acid-small molecule complexes provide insight into both the principles of molecular recognition by this class of biopolymers and the architecture of tertiary motifs in nucleic acid folding. Aptamers that recognize small molecules are increasingly applied as tools in molecular biology, from the detection of oxidative damage in DNA to conditional gene expression and from their use as modules for the engineering of allosteric ribozymes to biosensors.

Borrowing Ideas from Nature: Peptide Specific Binding to Gallium Arsenide

AbstractBiological systems have a unique ability to control crystal structure, phase, orientation and nanostructural regularity of inorganic materials. An example is seen with the control of crystallographic phase and orientation of calcium carbonate with the polyanionic proteins isolated from shells of the marine gastropod abalone. We are currently investigating the principles of natural biological molecular recognition in materials and developing new methods to pattern useful non-biological electronic and magnetic materials on new length scales. A peptide combinatorial approach has been employed to identify proteins that select for and specifically bind to inorganic structures such as semiconductor wafers, nanoparticles and quantum confined structures. This approach utilizes the inherent self-organizing, highly selective properties of biologically derived molecules. We are currently investigating peptide recognition and interaction with III-V and II-VI semiconductor materials, magnetic materials, calcium carbonates and phosphates. We have selected peptides that can specifically bind and discriminate between zinc-blende III-V semiconductor surfaces. These peptides show crystal face specificity and are being used to organize nanoparticle heterostructures. Long term potential application of these materials would include opto-electronic devices such as light emitting displays, optical detectors, lasers, and nanometer scale computer components.

Construction of a Blue Copper Analogue through Iterative Rational Protein Design Cycles Demonstrates Principles of Molecular Recognition in Metal Center Formation

The construction and characterization of a series of proteins in which the Blue Copper CysHis2Met primary coordination sphere was placed in various orientations within the hydrophobic core of thioredoxin has allowed exploration of the principles of molecular recognition between proteins and metals. An automated rational protein design algorithm predicted structurally suitable locations for these centers without use of either a potential preexisting binding site or any structural or sequence homology between the thioredoxin host and known Blue Copper proteins. A series of four primary designs and 32 variants were constructed. It was necessary to surround the designed primary coordination sphere with a hydrophobic shell to ensure the absence of potential alternative coordinating residues. Formation of a stable Cu(II)-thiolate bond required destabilization of a normally favored redox reaction in which the thiol is oxidized to a disulfide. This was achieved by more deeply burying the coordinating cysteine, pr...

The how and why of protein-carbohydrate interaction: a primer to the theoretical concept and a guide to application in drug design.

The common principles of molecular recognition with cooperative or bidentate hydrogen bonds, dispersion forces and hydrophobic packing govern the specificity of protein-carbohydrate interaction. Enthalpy/entropy-compensation is also valid, maintaining KD-values in the range of 30 mM to 200 nM. The individual contributions of the enthalpic and entropic factors which originate from the receptor, the ligand and/or the solvent to the overall free energy change can at least be estimated by a combination of computer-assisted molecular modeling, NMR spectroscopy of the reactants before and after complex formation and thermodynamic measurements. The delineation of adaptable parameters such as ligand or receptor side chain flexibility points to a route to practicable guidelines for a rational design of mimetics in glycosciences.

Molecular recognition of anions by synthetic receptors

Over the past year, several significant developments have been made in the field of anion binding. The fundamental principles of molecular recognition are increasingly being better understood, and of particular interest are reports of several synthetic anion receptors able to perform their task in complex natural media. Additionally, macroscopic devices such as anion specific electrodes and membranes based on a molecular recognition approach are now being made.

A new water soluble NMR shift reagent based on molecular recognition principles: Non-covalent π-π interactions of water soluble aromatic guest substrates with a biooronometallic host [Cp ∗Rh(2′-deoxyadenosine)] 3(OTf) j3

A new water soluble NMR shift reagent based on molecular recognition principles: Non-covalent π-π interactions of water soluble aromatic guest substrates with a biooronometallic host [Cp ∗Rh(2′-deoxyadenosine)] 3(OTf) j3

Chemical Library Purification Strategies Based on Principles of Complementary Molecular Reactivity and Molecular Recognition

A new methodology for solution-phase chemical library synthesis and purification is described. This approach applies fundamental properties of complementary molecular reactivity and recognition (CMR/R) as the basis for a general purification strategy. Specifically, parallel solution-phase reactions are purified by resins containing molecular recognition or molecular reactivity functionalities complementary to those of solution-phase reactants, reagents, and byproducts. When used in sequential or simultaneous combinations, various CMR/R resins remove excess reactants, reagents, and byproducts from solution-phase reaction products, which are isolated in purified form by filtration. Where reactions involve the need to remove byproducts or reagents that do not inherently contain sequestrable functionality, sequestration can be effected by the design and use of tagged reactants or reagents containing artificially-imparted molecular recognition functionality. An extension of this methodology utilizes CMR/R resi...

Metalloprotein design

The rational design of novel proteins offers a new method of studying structure and function, and makes possible the construction of new biomaterials. The richness of metal chemistry, the relative ease of creating stable complexes, and the remarkable degree of subtle, highly specific control of reactivity imposed by the protein matrix upon the metal center make metalloprotein design a very fruitful area for the exploration and application of design techniques. So far, most designs have concentrated on the exploration of simple metal-chelation properties. Even so, this has led to the development of new methods for protein stabilization and affinity purification, of metal biosensors, of novel strategies for control of protein activity, and of model systems for the exploration of fundamental principles of molecular recognition.

Molecular Recognition in the FMN – RNA Aptamer Complex

We report on a combined NMR – molecular dynamics calculation approach that has solved the solution structure of the complex of flavin mononucleotide (FMN) bound to the conserved internal loop segment of a 35 nucleotide RNA aptamer identified through in vitro selection. The FMN – RNA aptamer complex exhibits exceptionally well-resolved NMR spectra that have been assigned following application of two, three and four-dimensional heteronuclear NMR techniques on samples containing uniformly 13C, 15N-labeled RNA aptamer in the complex. The assignments were aided by a new through-bond NMR technique for assignment of guanine imino and adenine amino protons in RNA loop segments. The conserved internal loop zippers up through the formation of base-pair mismatches and a base-triple on complex formation with the isoalloxazine ring of FMN intercalating into the helix between a G·G mismatch and a G·U·A base-triple. The recognition specificity is associated with hydrogen bonding of the uracil like edge of the isoalloxazine ring of FMN to the Hoogsteen edge of an adenine at the intercalation site. There is significant overlap between the intercalated isoalloxazine ring and its adjacent base-triple platform in the complex. The remaining conserved residues in the internal loop participate in two G·A mismatches in the complex. The zippered-up internal loop and flanking stem regions form a continuous helix with a regular sugar – phosphate backbone except at a non-conserved adenine, which loops out of the helix to facilitate base-triple formation. Our solution structure of the FMN – RNA aptamer complex is to our knowledge the first structure of an RNA aptamer complex and outlines folding principles that are common to other RNA internal and hairpin loops, and molecular recognition principles common to model self-replication systems in chemical biology.

Binding in the growth hormone receptor complex.

Binding reactions between human growth hormone (hGH) and its receptor provide a detailed account of how a polypeptide hormone activates its receptor and more generally how proteins interact. Through high-resolution structural and functional studies it is seen that hGH uses two different sites (site 1 and site 2) to bind two identical receptor molecules. This sequential dimerization reaction activates the receptor, presumably by bringing the intracellular domains into close proximity so they may activate cytosolic components. As a consequence of this mechanism it is possible to build antagonists to the receptor by introducing mutations in hGH that block binding at site 2 and to build even more potent antagonists by combining these with mutants that enhance binding at site 1. Alanine-scanning mutagenesis of all contact residues at the site 1 interface shows that only a small and complementary set of side chains clustered near the center of the interface affects binding. The most important contacts are hydrophobic, and these are surrounded by polar and charged interactions of lesser importance. Kinetic analysis shows for the most part that the important side chains function to maintain the complex, not to guide the hormone to the receptor. Hormone-induced homodimerization or heterodimerization reactions are turning out to be pervasive mechanisms for signal transduction. Moreover, the molecular recognition principles seen in the hGH-receptor complex are likely to generalize to other protein-protein complexes.

High Affinity Carboxylate Binding Using Neutral Urea-Based Receptors with Internal Lewis Acid Coordination.

Uncharged receptors for anions and cations have many potential applications ranging from membrane transport carriers for ion-selective electrodes to reaction catalysts.1 As a consequence, there is a need to design and synthesize neutral receptors with high binding affinities and/ or high binding selectivities. Unlike cation receptors, there are essentially no examples of biotic, low molecular weight hosts for anions.2 Synthetic anion receptors have to be designed de novo using the principles of molecular recognition. The neutral anion-receptors reported to date have employed either Lewis acid-base,3 hydrogen bonding,4 and/or ion-dipole interactions.5 Most of the hydrogen bonding systems have used urea groups as the recognition motif. Urea-based hosts have been shown to associate with carboxylates, phosphates, and sulfonates to produce bidentate hydrogen-bonded complexes such as 1.4 In this paper we describe a structural design strategy that greatly improves the anion binding ability of neutral urea-based receptors. It is likely that this strategy can be incorporated into the designs of other amide-based molecular recognition systems. The formation of supramolecular complex 1 is driven primarily by hydrogen bonding and ion-dipole interactions.6,7 These bonding interactions can be strengthened by cooperative polarization of the urea group, which is accomplished by coordinating the urea carbonyl to a Lewis acid.8 A major design challenge is to ensure that the Lewis acid is held in the correct spatial orientation with a high effective molarity. One possible solution is the Lewis acid-urea conjugate 2. In line with our current interest in organoboron receptors,9 we designed boronate-urea 3 as a first-generation example of this receptor class. The valence bond structure for receptor 3 can be represented by two limiting forms, 3a or 3b. Prior to this study there was literature precedent to suggest that 3b would be the major resonance contributor.10

Molecular Recognition. The principle and recent chemical examples

Supramolecular chemistry is chemistry beyond the molecule, the designed chemistry of the intermolecular non-covalent bond, just as molecular chemistry is that of the covalent bond. This highly interdisciplinary field covers the chemical, physical and biological features of chemical species held together by non-covalent binding interactions. The selective binding of a substrate by a molecular receptor involves molecular recognition. It requires the design of receptors possessing steric and electronic features complementary to those of the substrate to be bound, together with a rigidity-flexibility balance suitable for the function to be performed. How well things fit together often depends on their predisposition, frequently referred to as preorganization. While the term implies entropic effects, it is hard to separate these from enthalpic factors of binding. Artificial host-guest systems as imitations of biological receptors demonstrate the principle of molecular recognition in its simplest form, while the self-assembly of small molecules to extended supramolecular structures requires a repetitive recognition process.

Design, synthesis, and evaluation of DNA minor groove binding agents: the duocarmycins

Abstract

Molecular recognition using conducting polymers: basis of an electrochemical sensing technology—Plenary lecture

Molecular recognition principles are being increasingly used as the basis for analytical technologies. The combination of a molecular recognition approach with conducting polymer materials has been beneficial, particularly in the field of electrochemical sensing. The electrochemical sensing process usually consists of two steps: analyte recognition and signal generation. Conducting polymers are versatile materials in which molecular/analyte recognition can be achieved in a number of different ways, including the incorporation of counter ions that introduce selective interactions, using the inherent and unusual ion-exchange properties of the conducting polymers; the addition of functional groups to the monomers; and the codeposition of metals within the polymer. Specific examples of these approaches are provided. The molecular recognition properties of conducting polymers can be further refined by the application of appropriate electrochemical potentials, which can induce either large or small changes in the chemical interactions that occur at the polymers. This electroactivity, as well as their conducting properties, also provides the basis for the signal generation steps. A number of electronic signals relating to some chemical or electrochemical change within the polymer can be measured. These include the faradaic electron transfer typically used for electrochemical sensing, the catalysis of the analytically useful electron transfer by the polymer or the analyte, the change in capacitance signals induced by the analyte species and changes in the polymer resistance which can be measured by a recently developed technique. These features, combined with the molecular recognition properties, make conducting polymers a very promising material for electrochemical sensing technology.

Molecular recognition and chemistry in restricted reaction spaces. Photophysics and photoinduced electron transfer on the surfaces of micelles, dendrimers, and DNA

This Account is concerned with molecular recognition in bimolecular reactions1 that occur in restricted spaces. Bimolecular reactions of interest are photoinduced electron transfers for which the reactants are positively electronically excited metal complexes (Figure 1) and another positively charged gegenion, either a metal complex or methyl viologen (MV^(2+)) that serves as an electron acceptor. The restricted reaction spaces are the interfacial regions of anionically charged polyions such as micelles, starburst dendrimers, and DNA. Molecular recognition is concerned with how specific sites on a molecular receptor are recognized by a binding substrate. Knowledge of the underlying principles of molecular recognition is useful in diverse activities such as the design of site- and conformation-specific reagents for biomolecules, the rational design of drugs and probes of polymer structure, the design of efficient catalytic systems, the design of strategies leading to the synthesis of new materials, and the design of novel nanoscopic devices.

Intelligent Chemical Systems Based on Conductive Electroactive Polymers

Conductive, electroactive polymers provide a unique platform upon which to construct intelligent materials. These polymers are capable of monitoring and respond ing to the chemical environment in which they are operational. They have properties which simplify the design and development of sensors, based on the principles of molec ular recognition. The conductive nature of the materials enables a range of electrical sig nals to be produced and this inherent electroactivity provides a unique means of triggering chemical responses. This article reviews the accomplishments of various workers in this field to demonstrate that conductive, electroactive polymers provide a basis for intelligent chemical systems.

Electrical properties of alpha-cyclodextrin metal iodide inclusion compounds

In order to build molecular scale mechanical or electronic devices it will be necessary to understand in atomic detail the general principles of molecular recognition and molecular self-assembly. Host-guest chemistry is essential for this understanding. The following short paper is a survey of electronic properties of molecular self-assembled cyclodextrin-metal iodide host-guest compounds. Alpha-cyclodextrin has the ability to crystallize into stacked channels which can act as hosts for the confinment of small guest molecules. The results of electrical studies on fifteen metal iodide cyclodextrin complexes are reported. These complexes consist of chains of polyiodide in the host lattice and metal atoms in the interspace regions. The conductivity is shown to vary, depending on the metal, between 10 −10 to 10 −4 S/cm at room temperature. When the samples are doped with excess iodine the conductivity decreases by about one order of magnitude for each metal iodide complex.