Theoretical studies on pro-leu-gly-nh2 conformation. (65/2747)

Classical potential function calculations were carried out on the hypothalamic factor Pro-Leu-Gly-NH2. The results indicate that the proposed 10-membered, hydrogen-bonded beta-turn conformation of this tripeptide is a strongly preferred structure. Its stability appears to be inherent in the rather rigid backbone conformation of the leucine residue rather than the hydrogen bond between the carboxamide proton of glycinamide and the C=O of the proline moiety; the glycinamide has little influence on the phi-psi of the leucine backbone structure. The type II beta-turn structure of the Pro-Leu-Gly-NH2 is preferred.  (+info)

Architecture with designer atoms: simple theoretical considerations. (66/2747)

The distinct electronic states of assemblies of metallic quantum dots are discussed in a simple approximation where each dot is mimicked as an "atom" that carries one valence electron. Because of their large size, the charging energy of the dots, I = energy required to add another electron, is much smaller than for ordinary atoms. The Coulomb blocking of charge migration is therefore easier to overcome. For the theory, however, this is a challenge, because ionic states, which are typically higher in energy, come down, so the density of electronic states is high, and special methods need to be adapted. Quantum dots are prepared by wet chemical methods and accordingly are not quite identical. They will have a size distribution that can be narrow (when the dots can be assembled into an ordered array) or broad. Other sources of disorder are packing imperfections, which are characteristic of a wider size distribution, ligand deformations, and chemical unevenness. Two experimental control parameters are the size of the dots and the spacing between them. We discuss the combined effects of the low charging energy and disorder and examine the distinct electronic phases that can be realized.  (+info)

Uncoupling of local field spectra in nuclear magnetic resonance: determination of atomic positions in solids. (67/2747)

Solid state nuclear magnetic resonance as a method of determining crystal structure has had limited success. Three distinct reasons for this failure can be identified when the resonance spectrum is of a dilute spin species in the presence of another abundant species. Two of these difficulties, and in part the third, can be mitigated by a family of coherent averaging techniques in double resonance, with considerably improved prospects for locating the rare spins with respect to their nearby neighbors. A particularly advantageous procedure is described and possible applications are discussed.  (+info)

Nuclear magnetic resonance study of heme-heme interaction in hemoglobin M Milwaukee: implications concerning the mechanism of cooperative ligand binding in normal hemoglobin. (68/2747)

Hemoglobin M Milwaukee (beta 67E11 val leads to Glu) is a naturally occurring valency hybrid containing two permanently oxidized hemes in the beta-chains. In this mutant, the two abnormal beta-chains cannot combine with oxygen, whereas the two alpha-chains are normal and can combine with oxygen cooperatively with a Hill coefficient of approximately 1.3. High-resolution proton nuclear magnetic resonance spectroscopy at 250 MHz has been used to investigate the hyperfine shifted resonances of the abnormal ferric beta-chains of Hb M Milwaukee over the spectral region from -30 to -60 parts per million from water at pD 7 and 30 degrees.  (+info)

Robust assessment of statistical significance in the use of unbound/intrinsic pharmacokinetic parameters in quantitative structure-pharmacokinetic relationships with lipophilicity. (69/2747)

The optimization of pharmacokinetic properties remains one of the most challenging aspects of drug design. Key parameters, clearance and volume of distribution, are multifactorial, which makes deriving structure-pharmacokinetic relationships difficult. The correction of clearance and volume of distribution for the unbound fraction in plasma is one approach taken that has enabled quantitative structure-pharmacokinetic relationships to be derived. Three published data-sets where unbound parameters have been correlated with lipophilicity have been reanalyzed. The reanalysis has shown that high correlation coefficients can be achieved without any true correlation in the data and can lead to misinterpretation of the ways in which lipophilicity influences pharmacokinetics. Randomization procedures are proposed as a more robust method of assessing significance.  (+info)

Molecular dynamics simulation of metallothionein-drug complexes. (70/2747)

The intermolecular interactions of metallothionein with nitrogen mustard drugs were studied by molecular dynamics simulations. Previous laboratory experiments have defined selective alkylation of two cysteine residues, and selective binding was proposed to precede alkylation. The present study provides information about accessibility to cysteines based on evaluating the intermolecular energies and distances in the first few ps of dynamics simulations. A series of dynamics simulations was performed with three drug molecules positioned at the eight most solvent accessible cysteine residues of the dimeric form of the protein. Sites proximal to the sulfhydryl groups of Cys-33 and Cys-48 were found to be the most favorable for complexing the aziridinium forms of chlorambucil, melphalan, and mechlorethamine. The sites for preferential binding are in qualitative agreement with the sites of selective alkylation defined experimentally.  (+info)

Sequential binding of CD11a/CD18 and CD11b/CD18 defines neutrophil capture and stable adhesion to intercellular adhesion molecule-1. (71/2747)

The relative contributions of CD11a/CD18 and CD11b/CD18 to the dynamics and strength of neutrophil adhesion to intercellular adhesion molecule (ICAM)-1-transfected cells were examined over the time course of chemotactic stimulation. Suspensions of neutrophils and transfectants were sheared in a cone-plate viscometer, and formation of heterotypic aggregates was measured by 2-color flow cytometry. The 2-body collision theory was used to compute adhesion efficiency, defined as the proportion of collisions between neutrophils and target cells that resulted in capture. ICAM-1 surface density and shear rate both regulated adhesion efficiency. Target cells expressing approximately 1000 ICAM-1 sites/microm(2) (I(low)) were captured with an efficiency of 0.15 at 100 s(-1), which decreased to zero at 300 s(-1). At 8-fold higher ICAM-1 expression (I(high)) corresponding to levels measured on interleukin-1-stimulated endothelium, efficiency was 0.3 at 100 s(-1) and remained above background to 900 s(-1). Shear alone was sufficient for CD11a/CD18-mediated adhesion to ICAM-1, and stimulation with formyl-methionyl-leucyl-phenylalanine boosted capture efficiency through CD11a/CD18 by 4-fold. In comparison, CD11b/CD18 supported one third of this efficiency, but was necessary for aggregate stability over several minutes of shear and at shear stresses exceeding 5 dyne/cm(2). Hydrodynamics influenced capture efficiency predominantly through the collisional contact duration, predicted to be approximately 9 milliseconds for successful capture of I(low) and 4 milliseconds for I(high). The implication is that an increase in ICAM-1 from resting levels to those on inflamed endothelium effectively increases the permissible shear in which capture through beta(2)-integrins may occur. Neutrophil adhesion to ICAM-1 appears to be a cooperative and sequential process of CD11a-dependent capture followed by CD11b-mediated stabilization.  (+info)

A relation between the principal axes of inertia and ligand binding. (72/2747)

The principal axes of inertia are eigenvectors that can be calculated for any rigid body. We report studies of the position of the principal axes in crystallographically solved protein molecules. We find with high frequency that at least one principal axis penetrates the surface of the respective protein in a region used for ligand binding. In antibody variable regions, an axis goes through the third hypervariable loop of the heavy chain. In major histocompatibility complex proteins, an axis goes through the peptide-binding groove. In protein-protein heterodimers, a principal axis of one subunit will often penetrate the interface formed with the other subunit. In many of these protein-protein complexes, the axis specifically intersects residues known to be critical for molecular recognition.  (+info)