Small Molecular Complexes Research Articles

Integrin Targeted MR Imaging

Magnetic resonance imaging (MRI) is a powerful medical diagnostic imaging modality for integrin targeted imaging, which uses the magnetic resonance of tissue water protons to display tissue anatomic structures with high spatial resolution. Contrast agents are often used in MRI to highlight specific regions of the body and make them easier to visualize. There are four main classes of MRI contrast agents based on their different contrast mechanisms, including T(1), T(2), chemical exchange saturation transfer (CEST) agents, and heteronuclear contrast agents. Integrins are an important family of heterodimeric transmembrane glycoproteins that function as mediators of cell-cell and cell-extracellular matrix interactions. The overexpressed integrins can be used as the molecular targets for designing suitable integrin targeted contrast agents for MR molecular imaging. Integrin targeted contrast agent includes a targeting agent specific to a target integrin, a paramagnetic agent and a linker connecting the targeting agent with the paramagnetic agent. Proper selection of targeting agents is critical for targeted MRI contrast agents to effectively bind to integrins for in vivo imaging. An ideal integrin targeted MR contrast agent should be non-toxic, provide strong contrast enhancement at the target sites and can be completely excreted from the body after MR imaging. An overview of integrin targeted MR contrast agents based on small molecular and macromolecular Gd(III) complexes, lipid nanoparticles and superparamagnetic nanoparticles is provided for MR molecular imaging. By using proper delivery systems for loading sufficient Gd(III) chelates or superparamagnetic nanoparticles, effective molecular imaging of integrins with MRI has been demonstrated in animal models.

Lee Pedersen s work in theoretical and computational chemistry and biochemistry

Nature at the lab level in biology and chemistry can be described by the application of quantum mechanics. In many cases, a reasonable approximation to quantum mechanics is classical mechanics realized through Newton's equations of motion. Dr. Pedersen began his career using quantum mechanics to describe the properties of small molecular complexes that could serve as models for biochemical systems. To describe large molecular systems required a drop-back to classical means and this led surprisingly to a major improvement in the classical treatment of electrostatics for all molecules, not just biological molecules. Recent work has involved the application of quantum mechanics for the putative active sites of enzymes to gain greater insight into the key steps in enzyme catalysis.

Revealing Noncovalent Interactions

Molecular structure does not easily identify the intricate noncovalent interactions that govern many areas of biology and chemistry, including design of new materials and drugs. We develop an approach to detect noncovalent interactions in real space, based on the electron density and its derivatives. Our approach reveals the underlying chemistry that compliments the covalent structure. It provides a rich representation of van der Waals interactions, hydrogen bonds, and steric repulsion in small molecules, molecular complexes, and solids. Most importantly, the method, requiring only knowledge of the atomic coordinates, is efficient and applicable to large systems, such as proteins or DNA. Across these applications, a view of nonbonded interactions emerges as continuous surfaces rather than close contacts between atom pairs, offering rich insight into the design of new and improved ligands.

Counting Constituents in Molecular Complexes by Fluorescence Photon Antibunching

Modern single molecule fluorescence microscopy offers new, highly quantitative ways for studying the systems biology of cells while keeping the cells healthy and alive in their natural environment. In this context, a quantum optical technique, photon antibunching, has found a small niche in the continuously growing applications of single molecule techniques to characterize small molecular complexes. Here, we review some of the most recent applications of photon antibunching in biophotonics research, and we provide a guide for how to conduct photon antibunching experiments at the single molecule level by applying techniques borrowed from time-correlated single photon counting (TCSPC). We provide a number of new examples for applications of photon antibunching to the study of multichromophoric molecules and small molecular complexes.

Evaluation of Dendritic Gadolinium Complexes as MRI Contrast Agents

A series of dendritic gadolinium complexes based on dendrimers with 1,4,7,10-tetraazacyclododecane as the core were synthesized. Both diethylenetriaminepentaacetic acid and pyridoxamine were incorporated to the amine groups on the surface to give the dendritic ligands. These dendritic ligands were then reacted with gadolinium chloride to yield the corresponding dendritic gadolinium complexes. The dendritic ligands and their gadolinium complexes were characterized by 1HNMR, IR, UV and elemental analysis. Relaxivity studies showed that the dendritic gadolinium complexes have higher relaxation effectiveness than that of the clinically used small molecular gadolinium complexes. Magnetic resonance imaging of the liver in rats indicated that the dendritic gadolinium complex containing pyridoxamine enhances the image contrast of the liver, provides prolonged intravascular duration and produces highly contrasted visualization of blood vessels in the liver.

Conformations and Binding Modes of 2,3,5,6-Tetra(2‘-pyridyl)pyrazine

The compound 2,3,5,6-tetra(2‘-pyridyl)pyrazine (tppz) is a remarkably versatile electron donor that displays a wide variety of binding modes. Quantum mechanical calculations on the 14 low energy conformations of tppz indicate a preference for four conformations in methanol and two others in either the gas phase or benzene. The prevalence of a species in solution and its predicted solubility, based on simple dipole moment considerations, provides an explanation for the isolation of different tppz polymorphs from the two solvents. Using a simple system for describing the tppz geometry, a review of previously reported crystal structures of complexes containing tppz as a ligand was conducted. The literature reveals a variety of tppz binding modes, including mono-, bi-, and tridentate coordination to a variety of Lewis acids. In addition to small molecular complexes, tppz-containing macrocycles and one-, two-, and three-dimensional extended chain systems have been characterized. Upon the basis of the analysis of tppz coordination behavior, several new binding modes are proposed that could be used for the construction of novel tppz complexes and supramolecular systems.

Control of photodissociation: vibrational mode selection and quantum interference

We present two methods for using lasers to control the photodissociation of small molecules and molecular complexes. The first method, which involves ternary aniline cluster cations consisting of aniline, water, and an aromatic molecule (benzene or pyrrole), utilizes the strong interaction between an NH stretching vibration and an adjacent hydrogen bond The infrared predissociation reactions of the cluster cations were investigated. Upon absorption of an infrared photon, the clusters dissociated and eliminated either water or the aromatic molecule. Measurements of the branching ratio for this reaction revealed that fission of the hydrogen bond was accelerated by excitation of the NH stretching vibration adjacent to the targeted hydrogen bond. The second method involves coherent control in the frequency domain. We investigated interference effects on the two-color dissociation of IBr using the fundamental (560 nm) and its second harmonic (280 nm). In the strong-excitation regime by the fundamental light (∼ 1.3×10 10 W cm −2 ), the yield of iodine atoms from IBr oscillated with the relative phase of the 560 and 280 nm light, whereas no change was observed in its angular distribution. This phase-dependent behavior can be explained by interference between the one-photon transition induced by the second-harmonic light and the dipole-forbidden two-photon transition induced by the strong fundamental light.

Microstructure of N-Picolylpolyurethane Transition Metal Complexes

Spectroscopic methods are used to investigate coordination structure of N-picolylpolyurethane transition metal complexes (PUPYM, M = Co2+ and Ni2+). Geometrical arrangement of ligands in first-shell coordination sphere of metal ions is postulated to be tetrahedral CoL2Cl2 and octahedral NiL2Cl2Z2, where L is the picolyl group and Z is a hydrate. From extended X-ray absorption fine structure (EXAFS) analysis, bond lengths for metal−chlorine and metal−ligand of PUPYM are similar to those of small molecular weight transition metal complexes. A two-phase model of PUPYM, which best describes the experimental data of DMTA and SAXS, is proposed. One microphase is the hard domain of self-segregated hard segments brought about by metal−ligand interaction, and the other phase is the matrix of soft segments. Transition metal ion−ligand moieties and their interactions dominate the macroscopic thermal behavior of PUPYM. The ligand field stabilization energy difference (ΔLFSE) between metal d-electrons in complexes with two picolyl ligands in the coordination sphere of metal ions and complexes maintaining one picolyl ligand as coordination pendent group is calculated on the basis of observed coordination structure, and it represents the energy supplied to split coordination cross-links. ΔLFSE of polyurethane nickel(II) complex is larger than that of the cobalt(II) complex. Since the mobility of hard segments is in inverse proportion to the strength of coordination cross-links, a higher α-transition temperature of PUPYNi2+ with respect to PUPYCo2+ is found as expected.

HSP27 Multimerization Mediated by Phosphorylation-sensitive Intermolecular Interactions at the Amino Terminus

Distinct biochemical activities have been reported for small and large molecular complexes of heat shock protein 27 (HSP27), respectively. Using glycerol gradient ultracentrifugation and chemical cross-linking, we show here that Chinese hamster HSP27 is expressed in cells as homotypic multimers ranging from dimers up to 700-kDa oligomers. Treatments with arsenite, which induces phosphorylation on Ser15 and Ser90, provoked a major change in the size distribution of the complexes that shifted from oligomers to dimers. Ser90 phosphorylation was sufficient and necessary for causing this change in structure. Dimer formation was severely inhibited by replacing Ser90 with Ala90 but not by replacing Ser15 with Ala15. Using the yeast two-hybrid system, two domains were identified that were responsible for HSP27 intermolecular interactions. One domain was insensitive to phosphorylation and corresponded to the C-terminal alpha-crystallin domain. The other domain was sensitive to serine 90 phosphorylation and was located in the N-terminal region of the protein. Fusion of this N-terminal domain to firefly luciferase conferred luciferase with the capacity to form multimers that dissociated into monomers upon phosphorylation. A deletion within this domain of residues Arg5-Tyr23, which contains a WDPF motif found in most proteins of the small heat shock protein family, yielded a protein that forms only phosphorylation-insensitive dimers. We propose that HSP27 forms stable dimers through the alpha-crystallin domain. These dimers further multimerize through intermolecular interactions mediated by the phosphorylation-sensitive N-terminal domain.

Electric-field-enhanced laser-induced plasma spectroscopy of jet-cooled metal-based ion–molecule complexes

Electric-field-enhanced laser-induced plasma spectroscopy is a relatively simple and general approach to the mapping of electronic states and internal mode structure in small metal-based molecular complexes. In an exemplary study, weakly bound excited-state ion–molecule complexes of aluminum have been formed and monitored. Emission spectra associated with Al+CO(Al+OC) and Al+H2 complexation show clear vibrational structure tentatively associated with the Al+ -molecule stretch and/or triatomic bending mode. These features are correlated precisely with transitions among several excited states of the Al+ ion which extend throughout the visible and ultraviolet. Evidence is also obtained for Al+N2 complexation associated with select Al+ excited states. All complex emissions which can be readily ascribed involve singlet-(Al+) –singlet-(CO,H2,N2) interactions. Resulting singly charged electronically excited molecular-ion complexes are likely formed in orbiting collisions of the Al+ ion. Observed vibrational-level separations are consistent with quantum-chemical calculations on the ground electronic 1Σ states of Al+CO, Al+OC, Al+H2, and Al+N2. Broadening and vibrational structure associated with an Al++–N2 interaction are apparent, as excited-state complex formation in this system dominates that for the Al++–CO interaction. These results are considered in view of an anticipated Coulomb explosion in multiply charged ions. Extensions to the vacuum ultraviolet for the study of weakly bound ground-state Al+ complexes and extrapolations to other metal-based systems are suggested.

The Effect of a Protein Environment on the Proposed Activation Mechanism of the Histamine H2‐Receptor

AbstractLack of information on the molecular structures of receptor proteins hampers the development of an understanding of their mechanisms. Small molecular models have served in the study of discrete details of such mechanisms, but receptor processes like recognition and activation take place in the protein environment of the receptor which may have a role in the process. To learn about the possible role of the protein environment in these mechanisms, we followed a heuristic approach in which models are used that range from small molecular complexes to macromolecular environments that model the receptors. The underlying assumption in such modelling is that similar elements of secondary structure, present in the model proteins as well as in the receptors, will make similar contributions to the molecular mechanism in which they function. We report the results of computational simulations of the activation mechanisms in a model protein environment used to study the effect of the protein structure on the proposed activation mechanism of the H2‐receptor of the neurotransmitter histamine. The Protein Data Bank was searched for a protein of known structure that could serve as a model for a macromolecular environment of the histamine H2‐receptor, based on a series of requirements defined by findings from our previous work on small molecular complexes modelling recognition and activation mechanisms in that receptor. The enzyme citrate synthase, E.C. 4.1.3.7, was found to contain the structural elements necessary for such a model. The activation mechanism simulated inside this protein consists of two proton transfer steps: one from the receptor to the neurotransmitter and another from it to a different site of the receptor. Quantum chemical methods were used to calculate the energetics of the proton transfers inside the protein structure represented as a collection of point charges and polarizable dipoles included in the Hamiltonian. The energetic contribution from polarization, as well as the interaction of the proton transfer system with the helix dipoles, is found to affect the proton transfer mechanism. The results suggest protein engineering approaches that can be used to modulate receptor activity by specific changes in the protein structure.

Limiting behavior of partition functions of models with quadratically dependent energy spectra and consequences regarding theoretical study of chemical reactivity

AbstractThe conventional partition functions of models with quadratically dependent energy spectra (e.g., translation in a box or free internal rotation), which are widely used in literature, exhibit an incorrect limit behavior in the region of low temperatures and/or small values of the characterizing molecular parameter. In particular, this leads to the absurd value —∞ for the contribution of these motions to the entropy term at these limit conditions. This incorrect behavior appears to be due to the replacement of rigorous summation by integration in conventional derivation of these partition functions. The derived improved practical formulas with the correct limit behavior indicate that it will be necessary to carry out quite substantial numerical corrections in the case of many reactivity characteristics reported in the literature. Particularly, the improved formulas should be applied with (small) molecular complexes at the typical temperatures of their observation, e.g., van der Waals molecules with free internal rotation. Simultaneously discussed is the possibility of application of the functional relation valid for a rigorous partition function of the considered type of energy spectrum. The reasoning in the case of the translational partition function indicates that, in principle, it can depend on the vessel shape. Possible consequences for thermodynamics of the ideal gas are analyzed.

In vitro estimation of the effects of selected proteins on iron bioavailability

The effects of proteins and protein digestion products on iron bioavailability were studied. Iron dialyzability, under simulated gastrointestinal conditions, in the presence of selected proteins and fractionated protein digestion products, was used as a measure of iron bioavailability. Dialyzability was high for bovine serum albumin and beef, intermediate for egg albumin, and low for soy flour, gelatin, casein, soy protein isolate, and gluten. Low molecular weight digestion product fractions from bovine serum albumin and beef enhanced iron dialysis; similar fractions from casein and soy protein isolate did not affect iron dialysis. The influence of proteins on iron bioavailability appears to be related to the affinity of undigested or partially digested protein for iron and to the stability of small molecular weight soluble iron complexes formed from protein digestion products.

The theory of condensation of supersaturated vapours in the absence of ions

A brief review of the condensation theory of Becker & Döring (1935) and Frenkel (1946) is given. It is shown that the theory is subject to the limitation that it assumes that small molecular complexes behave like liquid droplets. This is not the case for complexes consisting of a few molecules only, so that the rate of condensation expected from the theory may be altered by an appreciable amount. The Becker & Döring expression for critical supersaturation is compared with the cloud-chamber measurements of Volmer & Flood (1934), taking into account the rapid heating of the gas after the fast expansion. It is found to be in approximate agreement for water and some of the alcohols, but methyl alcohol, benzene and carbon tetrachloride show large discrepancies. More measurements of critical supersaturations are needed.