Guest encapsulation and self-assembly of molecular capsules in polar solvents via multiple ionic interactions

Herein we report the formation and characterization of a novel type of capsules resulting from the self-association between oppositely charged complementary building blocks in MeOH/H2O. The assembly is based on the interaction between tetraamidinium calix[4]arenes 1a-d and tetrasulfonato calix[4]arene 2. Evidence for the formation of the expected 1:1 assemblies is provided by proton NMR, ESI-MS, and ITC. The association process is fast on the NMR time scale and strongly entropy driven, with association constants in the range of 10(6) M-1. The system 1a.2 shows binding affinity toward acetylcholine, tetramethylammonium, and N-methylquinuclidinium cations.     

Kinetic stabilities of double,tetra-, and hexarosette hydrogen-bonded assemblies

A study of the kinetic stabilities of hydrogen-bonded double, tetra-, and hexarosette assemblies, comprising 36, 72, and 108 hydrogen bonds, respectively, is described. The kinetic stabilities are measured using both chiral amplification and racemization experiments. The chiral amplification studies show that solvent polarity and temperature strongly affect the kinetic stabilities of these hydrogen-bonded assemblies. For example, the activation energy for the dissociation of a tetramelamine from a tetrarosette assembly, a process that involves the breakage of 24 hydrogen bonds, was determined at 98.7 +/- 16.6 kJ mol(-1) in chloroform and 172.8 +/- 11.3 kJ mol(-1) in benzene. Moreover, racemization studies with enantiomerically enriched assemblies reveal a strong dependence of the kinetic stability on the number and strength of the hydrogen bonds involved in assembly formation. The half-lives for double, tetra-, and hexarosette assemblies were found to be 8.4 min, 5.5 h, and 150 h in chloroform at 50 degrees C, respectively. For higher generations of these types of assemblies, the kinetic stabilities become so high that they can no longer measured in a direct manner.     

The agonistic binding site at the histamine H2 receptor. I. Theoretical investigations of histamine binding to an oligopeptide mimicking a part of the fifth transmembrane α-helix

Summary Mutation studies on the histamine H₂ receptor were reported by Gantz et al. [J. Biol. Chem., 267 (1992) 20840], which indicate that both the mutation of the fifth transmembrane Asp¹⁸⁶ (to Ala¹⁸⁶) alone or in combination with Thr¹⁹⁰ (to Ala¹⁹⁰) maintained, albeit partially, the cAMP response to histamine. Recently, we have shown that histamine binds to the histamine H₂ receptor as a monocation in its proximal tautomeric form, and, moreover, we suggested that a proton is donated from the receptor towards the tele-position of the agonist, thereby triggering the biological effect [Nederkoorn et al., J. Mol. Graph., 12 (1994) 242; Eriks et al., Mol. Pharmacol., 44 (1993) 886]. These findings result in a close resemblance with the catalytic triad (consisting of Ser, His and Asp) found in serine proteases. Thr¹⁹⁰ resembles a triad's serine residue closely, and could also act as a proton donor. However, the mutation of Thr¹⁹⁰ to Ala¹⁹⁰ — the latter is unable to function as a proton donor — does not completely abolish the agonistic cAMP response. At the fifth transmembrane -helix of the histamine H₂ receptor near the extracellular surface, another amino acid is present, i.e. Tyr¹⁸², so an alternative couple of amino acids, Tyr¹⁸² and Asp¹⁸⁶, could constitute the histamine binding site at the fifth -helix instead of the (mutated) couple Asp¹⁸⁶ and Thr¹⁹⁰. In the first part of our present study, this hypothesis is investigated with the aid of an oligopeptide with an -helical backbone, which represents a part of the fifth transmembrane helix. Both molecular mechanics and ab initio data lead to the conclusion that the Tyr¹⁸²/Asp¹⁸⁶ couple is most likely to act as the binding site for the imidazole ring present in histamine.     

Enantioselective noncovalent synthesis of hydrogen-bonded double-rosette assemblies

The noncovalent synthesis of enantiomerically pure hydrogen-bonded assemblies (M)- and (P)-1(3).(CA)(6) is described. These dynamic assemblies are of one single handedness (M or P), but do not contain any chiral components. They are prepared by using the "chiral memory" concept: the induction of supramolecular chirality is achieved through initial assembly with chiral barbiturates, which are subsequently replaced by achiral cyanurates. This exchange process occurs quantitatively and without loss of the M or P handedness of the assemblies. Racemization studies have been used to determine an activation energy for racemization of 105.9+/-6.4 kJ mol(-1) and a half-life time to racemization of 4.5 days in benzene at 18 degrees C. Kinetic studies have provided strong evidence that the rate-determining step in the racemization process is the dissociation of the first dimelamine component 1 from the assembly 1(3).(CA)(6). In addition to this, it was found that the expelled chiral barbiturate (RBAR or SBAR) acts as a catalyst in the racemization process. Blocking the dissociation process of dimelamines 1 from assembly 1(3).(CA)(6) by covalent capture through a ring-closing metathesis (RCM) reaction produces an increase of more than two orders of magnitude in the half-life time to racemization.     

Complexation of Porphyrin-Appended Guests by Calix[4]arene-Appended Cyclodextrins

A calix[4]arene based -cyclodextrin dimerand tetramer (1 and2, Figure 1) were synthesized by covalentattachment of amono(2-O-xylylamino)--cyclodextrinderivative to calix[4]areneplatforms, bi- or tetrafunctionalized withcarboxylic acid groups at their upperrims. The complexation of porphyrin-basedguest molecules by these hosts inwater was studied using microcalorimetry.Tetrakis(4-phenylsulfonato)porphyrin(TsPP) binds to 2 in a 1 : 2 (host : guest)fashion with enhanced bindingstrength (K₁ = 6.6 × 10⁶ M ^-1) ascompared to the monomeric TsPP–CDinteraction (K = 8.8 × 10⁵ M ^-1). Thisenhancement is attributed tothe involvement of two cyclodextrin units in theaccommodation of one TsPP guest.Increase of the number of 4-sulfonatophenyl siteson the guest by generating the-oxo-dimer of the iron(III) complex of TsPPled to further increase of thebinding strength owing to participation of three-cyclodextrin cavities of2 (K = 1.5 × 10⁷ M ^-1). The geometricincompatibility betweenhost and guest, stemming from the fact that both TsPPand its -oxo-dimer arefairly small compared to the multi-cyclodextrin hosts,probably explains why theenhancement is still moderate. A much more pronouncedincrease in complexationstrength was achieved with p- and m-pyridylporphyrinextended withp-tert-butylbenzyl guest sites. Theseguests are large enough to accommodatethree to four -cyclodextrin units. The bettermatch in size between host and guestgave association constants up 10⁸ and 10⁹ M ^-1for the -cyclodextrindimer and tetramer, respectively. In fact, the 1 : 1complex betweentetrakis(p-tert-butylbenzyl)-p-pyridylporphyrinand 2(K = 5 × 10⁹ M ^-1) is the strongestreported for cyclodextrin–porphyrininteractions.     

Direct bandgap optical transitions in Si nanocrystals

The effect of quantum confinement on the direct bandgap of spherical Si nanocrystals has been modelled theoretically. We conclude that the energy of the direct bandgap at the Γ-point decreases with size reduction: quantum confinement enhances radiative recombination across the direct bandgap and introduces its “red“ shift for smaller grains. We postulate to identify the frequently reported efficient blue emission (F-band) from Si nanocrystals with this zero-phonon recombination. In a dedicated experiment, we confirm the “red“ shift of the F-band, supporting the proposed identification.     

Quantitative visualization of high-speed 3D turbulent flow structures using holographic interferometric tomography

Using holographic interferometry the three-dimensional structure of unsteady and large-scale motions within subsonic and transonic turbulent jet flows has been studied. The instantaneous 3D flow structure is obtained by tomographic reconstruction techniques from quantitative phase maps recorded using a rapid-switching, double reference beam, double pulse laser system. The reconstruction of the jets studied here reveal a three-dimensional nature of the flow. In particular an increasing complexity can be seen in the turbulence as the flow progresses from the jet nozzle. Furthermore, a coherent three-dimensional, possibly rotating, structure can be seen to exist within these jets. The type of flow features illustrated here are not just of fundamental importance for understanding the behavior of free jet flows, but are also common to a number of industrial applications, ranging from the combustion flow within an IC engine to the transonic flow through the stages of a gas turbine.     

Mapping of a discontinuous and highly conformational binding site on follicle stimulating hormone subunit-β (FSH-β) using domain Scan™ and Matrix Scan™ technology

This paper describes the application of two novel screening technologies, i.e. Domain Scan (24- and 30-mer peptides) and Matrix Scan (24-mer peptides) technology, in the mapping of a discontinuous epitope on FSH-beta for a series of 20 monoclonal antibodies. 11 out of 20 mAb's, mapping of which was not successful by conventional Pepscan technology (12-mer peptides), showed selective binding to peptide-constructs corresponding to the beta3-loop of FSH in the Domain and/or Matrix Scan. Systematic replacement analysis studies with peptide-construct 57VYETVRVPGCAC-SAc-ADSLYTYPVATQ81 revealed that for most mAb's the amino acids R62, A70, D71, and L73 form the core of the epitope. A Domain Scan performed in the C-O format showed highly selective binding for mAb's 1 and 2 with only three beta1-beta3 peptide-constructs covering the residues 60TVRVPGCAHHADSLY74 in combination with 10IAIEKEECRFAI21, while for mAb 10 binding was observed with peptide-constructs containing the C-terminal residues 97RGLGPSYCSFGEMKE114 in combination with the residues 10IAIEKEECRFAI21. A Matrix Scan of mAb 17 showed that peptides from four different regions on FSH (1st strand beta3-loop, alpha 1-loop, long alpha2-loop, det. loop) showed enhanced binding in combination with several 70ADSL73-containing peptides. BIACORE measurements with mAb's 1, 2, 13, and 17 using a set of 21 different peptide(-construct)s partially confirmed the Domain and Matrix Scan screening results. Only 24- and 33-mer peptides covering both the 1st and 2nd strand of the beta3-loop showed measurable binding. Cyclic beta3-loop peptide mimics were found to bind significantly stronger (Kd approximately 5 microM) than the lineair analogues, in agreement with the fact that the discontinuous epitope is part of a loop structure. Coupling of the lineair beta1-peptide 1oIAIEKEECRFAI21 to the linear beta3-peptide *52TFKELVYETVRVPGCAHHADSLYTYPVATQAH83# via disulfide bond formation showed a 2-3 fold increase in Kd, thus conforming participation of the beta 1-loop in antibody binding for these mAb's.     

Bioactive peptides based on diversity libraries, supramolecular chemistry and rational design: A new class of peptide drugs. Introduction

A new class of pharmaceutical molecules--synthetic vaccines, synthetic diagnostics and peptide drugs--are emerging based on recent advances of peptide libraries, supramolecular chemistry and rational design. The molecules of this growing class have exciting potential, not met by classical drugs based on small molecules or recombinant proteins.     

Recognition of caffeine in aqueous solutions

Binding of caffeine in aqueous solutions has been achieved for the first time by using water-soluble, tetracationic peptide-porphyrin conjugates Zn-1 as the receptor molecules. The association constant for caffeine with receptor Zn-1 is in some cases as high as 6000 M(-1), only 5-6 times lower than the highest binding constant reported for an artificial caffeine receptor in low polarity aprotic solvents. The binding mechanism has been studied by a combination of experimental techniques such as UV-visible and NMR spectroscopy and microcalorimetry. Recognition of caffeine involves both stacking with the porphyrin ring and metal coordination. Subtle variations of the receptor structure affect the complexation. Receptors Zn-1 have also been investigated for the recognition of molecules structurally related to caffeine, for example, 1-methylimidazole. Selectivity towards oxopurine derivatives (caffeine and theophylline) have been found.