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PubMed2006

Haptic applications for molecular structure manipulation.

We describe the application of haptic technology to enhance the information available in chemical systems, specifically related to computational drug design. These methods are designed to build upon the visual information presented by molecular viewers and add the sensation of touch, or force feedback. The addition of sensory input can aid in the analysis of molecular structures and the understanding of intermolecular interactions by delivering chemically relevant forces to the end user.

Computer Graphics↗
PubMed1994

Molecular structure and function of angiotensin type 2 receptor.

More than two isoforms have been identified for angiotensin receptors based on their ligand selectivity. The objective of this study is to determine the molecular structure of angiotensin type 2 receptor (AT2), whose physiological functions are still an enigma despite extensive studies on its distribution in fetal tissues. We expression-cloned a cDNA of an affinity-purified AT2 from rat pheochromocytoma cells (PC12w). The AT2 cDNA clone comprises 2,868 nucleotides and encodes a 363 amino acid protein with seven putative transmembrane domains. The dissociation constant for its binding to 125I-CGP42112A, an AT2-specific ligand, was 0.11 +/- 0.01 nM. Its binding to 0.5 nM 125I-[Sar1,Ile8]-Ang II was not inhibited by Dup 753 but by PD123319 (IC50 = 1.7 +/- 0.2 nM). These binding features are characteristic of angiotensin type 2 receptor. The amino acid sequence analysis of the purified AT2 corroborated the amino terminus of the deduced primary structure of AT2. Angiotensin type 1 receptor (AT1) is the most closely related to AT2 but with only 32% amino acid sequence identity. Angiotensin II attenuated membrane-associated protein tyrosine phosphatase activity in the COS-7 cells stably expressing AT2 through a pertussis toxin-sensitive G protein. However, the physiological function of AT2 in the fetal kidney is still unresolved.

Amino Acid Sequence↗
PubMed1991

Latent forms of TGF-beta: molecular structure and mechanisms of activation.

TGF-beta proteins are produced as latent, high molecular weight complexes. The latent form of TGF-beta 1 (L-TGF-beta 1) in human platelets comprises three components: the mature TGF-beta 1 molecule, the N-terminal remnant of the TGF-beta 1 precursor in dimeric form and a novel component denoted TGF-beta 1-binding protein (TGF-beta 1-BP). Recombinant TGF-beta 1 expressed in CHO cells, which lacks TGF-beta 1-BP, is also produced as a latent form. Thus, the N-terminal remnant of the TGF-beta 1 precursor is sufficient for TGF-beta 1 latency, and it was denoted TGF-beta 1 latency-associated peptide (TGF-beta 1-LAP). The cDNA for TGF-beta 1-BP has been cloned. It is mainly composed of two different kinds of repeat sequences, i.e. 16 epidermal growth factor-like repeats and three copies of a cysteine-rich repeat hitherto not found in other proteins. The function of TGF-beta 1-BP remains to be elucidated. Activation of L-TGF-beta can be achieved by different chemical and enzymic treatments, or by incubation with certain cell types. Understanding of the physiological activation mechanisms and the in vivo roles of L-TGF-beta will be important for future clinical applications of TGF-beta.

Animals↗
PubMed2000

The E-state as the basis for molecular structure space definition and structure similarity

The electrotopological state (E-state) is presented as a representation of molecular structure useful for definition of a space for chemical structures. This E-state representation provides the basis for chemical database management. The E-state formalism is presented along with its extension to the atom-type E-state. An approach to database organization, using polychlorobiphenyls (PCBs) as examples, reveals the descriptive power of the E-state paradigm. A well-organized chemical database, as described here, may be searched to find structures similar to a target structure with the expectation that such structures may exhibit properties similar to the target. Searches using the atom-type E-state indices are demonstrated with two example drug molecules.

Journal Article↗
PubMed2002

Molecular structures of five-coordinated halide ligated iron(III) porphyrin, porphycene, and corrphycene complexes.

Molecular structures of 12 porphyrin analogues, Fe(III)(EtioP)X(1(a)-1(d)), Fe(III)(EtioCn)X(2(a)-2(d)), and Fe(III)(Etio-Pc)X(3(a)-3(d)), where X = F (a), Cl (b), Br (c), and I (d), are determined on the basis of X-ray crystallography. Combined analyses using Mössbauer, (1)H NMR, and EPR spectroscopy as well as SQUID magnetometry have revealed that 3(d) exhibits a quite pure S = 3/2 spin state with a small amount of an S = 5/2 spin admixture. In contrast, all the other complexes show the S = 5/2 spin state with a small amount of the S = 3/2 spin admixture. The structural and spectroscopic data indicate a strong correlation between the spin states of the complexes and the core geometries such as Fe-N bond lengths, cavity areas, and DeltaFe values.

Journal Article↗
PubMed2006

Molecular structure and dynamics at the interfaces within bulk heterojunction materials for solar cells.

The molecular structures within the interfaces of the bulk heterojunction material comprising regioregular-poly(3-hexylthiophene-2,5-diyl), rrP3HT, and C(60) or its soluble derivative, [6,6]-phenyl-C(61)butyric acid methyl ester, PCBM, have been studied by one- and two-dimensional nuclear magnetic resonance (NMR). The local structure within the interface was inferred from chemical shift (CS) data obtained from composite films (CFs) fabricated at room temperature (PCBMCF-RT and C(60)CF-RT) and from CFs that had been subsequently annealed at 150 degrees C for 30 min (PCBMCF-A150 and C(60)CF-150A). In PCBMCF-RT, the alkyl side chains of rrP3HT are close to the C(60) ball; C(60) is essentially 'wrapped' by the alkyl side chains. In PCBMCF-A150, the alkyl side chains self-assemble such that rrP3HT and PCBM are separated. The observation of well-defined splittings in the CS spectrum of the (13)C of C(60) in C(60)CF-A150 indicates a distortion from spherical symmetry. Measurements of the spin-lattice relaxation rate, 1/T(1), of C(60) imply local magnetic field fluctuations that arise from the dynamics of the C(60) distortion.

Journal Article↗
PubMed2005

The molecular structure of [Sn(P2C2But2)] using gas-phase electron diffraction and DFT calculations.

The molecular structure of 2,4-di-tert-butyl-eta4-1,3-diphosphacyclobutadiene tin has been determined in the gas phase by electron diffraction using both the DYNAMITE and SARACEN methods. The suitability of many different theoretical methods for the calculation of structures of half-sandwich main-group metal complexes has been investigated, and, by comparison of the results with the experimental structures, suggestions have been made as to the most suitable methods for this class of compound.

Journal Article↗
PubMed1988

Crystal and molecular structure of the ammonium salt of the dinucleoside monophosphate d(CpG).

The crystal and molecular structure of the ammonium salt of deoxycytidylyl-(3'-5')-deoxyguanosine has been determined from 0.85 A resolution single crystal X-ray diffraction data. The crystals obtained by acetone diffusion technique at -20 degrees C, are orthorhombic, P212121, a = 12.880(2), b = 17444(2) and c = 27.642(2) A. The structure was solved by high resolution Patterson and Fourier methods and refined to R = 0.136. There are two d(CpG) molecules in the asymmetric unit forming a mini left handed Z-DNA helix. This is in contrast to the earlier reported forms of d(CpG) where the molecules form self base paired duplexes. There are two ammonium ions in the asymmetric unit. The major groove NH+4 ion interacts with N7 of guanines through water bridges besides making H-bonded interactions directly with the phosphate oxygen atoms. A second NH+4 ion is found in the minor groove interacting directly with the phosphate oxygen atoms. Symmetry related molecules pack in such a way that the cytosine base stacks on cytosine and guanine base on guanine. Our structure demonstrates that alternating d(CpG) sequences have the ability to adopt the left handed Z-DNA structure even at the dimer level i.e., in a sequence which is only two base pairs long.

Ammonia↗
PubMed1991

Molecular structure of charybdotoxin: retraction.

Shortly after our paper of 3 August 1990 on the molecular structure of charybdotoxin (1) was published, two independent determinations of the structure of this molecule appeared (2) that were similar to each other and in strong disagreement with ours. We have obtained new data and find that some spectral features depend on solvent conditions, which explains some differences between our data and those of the other groups. More important, we conclude that we most probably misassigned an important sequence of amino acids, as suggested by Bontems et al.(3). Therefore, we withdraw our previously reported structure (1) and regret any inconvenience it may have caused. We thank F. Toma for sending us a copy of his paper before publication and for discussions.

Journal Article↗
PubMed1990

Crystal and molecular structure of a DNA duplex containing the carcinogenic lesion O6-methylguanine.

The crystal and molecular structure of the first DNA duplex containing the carcinogenic lesion O6MeG has been determined to a resolution of 1.9 A and refined to an R factor of 19%. (d[CGC-(O6Me)GCG])2 crystallizes in the left-handed Z DNA form and has crystal parameters and conformational features similar to those of the parent sequence [d(CG)3]2. The methyl groups on O6 of G4 and G10 have C5-C6-O6-O6Me torsion angles of 73 degrees and 56 degrees, respectively, and protrude onto the major groove surface. The base-pairing conformation for the methylated G.C base pairs is of the Watson-Crick type as opposed to a wobble-type conformation that had been proposed in a B DNA fragment. As in other Z DNA structures, a spine of hydration is seen in the minor groove.

Crystallization↗
PubMed2002

Prediction of human clearance from animal data and molecular structural parameters using multivariate regression analysis.

The aim of the study reported here was to develop a method for predicting human clearance that can be applied to various kinds of drugs using clearance values for rats and dogs and some molecular structural parameters. The clearance data for rats, dogs, and humans of 68 drugs were obtained from literature. The compounds have various structures, pharmacological activities, and pharmacokinetic characteristics. In addition, molecular weight, c log P, and the number of hydrogen bond acceptors were used as possible descriptors related to the human clearance value for each drug. Three types of regression methods, multiple linear regression (MLR) analysis, partial least squares (PLS) method, and artificial neural network (ANN), were used to predict human clearance, and their predictive performances were compared with allometric approaches, which have been widely used in interspecies scaling. In MLR and PLS analyses, interaction terms were introduced to evaluate the nonlinear relationships. For the data sets used in the present study, MLR and PLS with quadratic terms gave the same equation and the best predictive performance. The value of the squared cross-validated correlation coefficient (q(2)) was 0.682. In conclusion, the MLR method using animal clearance data from only two species and using easily calculated structural parameters can generally predict human clearance better than allometric methods. This approach can be applied to drugs with various characteristics.

Animals↗
PubMed2006

Molecular structure of amyloid fibrils: insights from solid-state NMR.

Solid-state nuclear magnetic resonance (NMR) measurements have made major contributions to our understanding of the molecular structures of amyloid fibrils, including fibrils formed by the beta-amyloid peptide associated with Alzheimer's disease, by proteins associated with fungal prions, and by a variety of other polypeptides. Because solid-state NMR techniques can be used to determine interatomic distances (both intramolecular and intermolecular), place constraints on backbone and side-chain torsion angles, and identify tertiary and quaternary contacts, full molecular models for amyloid fibrils can be developed from solid-state NMR data, especially when supplemented by lower-resolution structural constraints from electron microscopy and other sources. In addition, solid-state NMR data can be used as experimental tests of various proposals and hypotheses regarding the mechanisms of amyloid formation, the nature of intermediate structures, and the common structural features within amyloid fibrils. This review introduces the basic experimental and conceptual principles behind solid-state NMR methods that are applicable to amyloid fibrils, reviews the information about amyloid structures that has been obtained to date with these methods, and discusses how solid-state NMR data provide insights into the molecular interactions that stabilize amyloid structures, the generic propensity of polypeptide chains to form amyloid fibrils, and a number of related issues that are of current interest in the amyloid field.

Amino Acid Sequence↗
PubMed1995

The crystal and molecular structure of 2-sulfamino-2-deoxy-alpha-D-glucopyranose sodium salt.2H2O (glucosamine 2-sulfate).

The crystal and molecular structure of 2-sulfamino-2-deoxy-alpha-D-glucopyranose has been determined by direct methods. The crystal belongs to the space group P2(1)2(1)2(1) and has unit cell dimensions a = 7.713 A, b = 9.390 A and c = 17.222 A. The sugar ring has the expected conformation (4C1) and the geometry of the N-sulfate moiety is comparable with that found in previous investigations of monosaccharide O-sulfates. The sodium ion is octahedrally coordinated involving one ring oxygen, two hydroxyls, one sulfate oxygen and two water oxygens.

Carbohydrate Conformation↗
PubMed2001

Tissue engineering of functional cardiac muscle: molecular, structural, and electrophysiological studies.

The primary aim of this study was to relate molecular and structural properties of in vitro reconstructed cardiac muscle with its electrophysiological function using an in vitro model system based on neonatal rat cardiac myocytes, three-dimensional polymeric scaffolds, and bioreactors. After 1 wk of cultivation, we found that engineered cardiac muscle contained a 120- to 160-microm-thick peripheral region with cardiac myocytes that were electrically connected through gap junctions and sustained macroscopically continuous impulse propagation over a distance of 5 mm. Molecular, structural, and electrophysiological properties were found to be interrelated and depended on specific model system parameters such as the tissue culture substrate, bioreactor, and culture medium. Native tissue and the best experimental group (engineered cardiac muscle cultivated using laminin-coated scaffolds, rotating bioreactors, and low-serum medium) were comparable with respect to the conduction velocity of propagated electrical impulses and spatial distribution of connexin43. Furthermore, the structural and electrophysiological properties of the engineered cardiac muscle, such as cellularity, conduction velocity, maximum signal amplitude, capture rate, and excitation threshold, were significantly improved compared with our previous studies.

Animals↗
PubMed1994

Molecular structure of the oxidized high-potential iron-sulfur protein isolated from Ectothiorhodospira vacuolata.

The high-potential iron-sulfur protein (iso-form II) isolated from Ectothiorhodospira vacuolata has been crystallized and its three-dimensional structure determined by molecular replacement procedures and refined to 1.8-A resolution with a crystallographic R factor of 16.3%. Crystals employed in the investigation belonged to the space group C222(1) with unit cell dimensions of a = 58.4 A, b = 64.7 A, and c = 39.3 A and one molecule per asymmetric unit. Like those HiPIPs structurally characterized thus far, the E. vacuolata molecule contains mostly reverse turns that wrap around the iron-sulfur cluster with cysteine residues 34, 37, 51, and 65 ligating the metal center to the polypeptide chain. There are 57 ordered solvent molecules, most of which lie at the surface of the protein. Two of these water molecules play important structural roles by stabilizing the loops located between Asp 42 and Lys 57. The metal center binding pocket is decidedly hydrophobic with the closest solvent molecule being 6.9 A from S2 of the [4Fe-4S] cluster. The E. vacuolata HiPIP molecules pack in the crystalline lattice as dimers with their iron-sulfur centers approximately 17.5 A apart. On the basis of biochemical properties, it was anticipated that the E. vacuolata HiPIP would be structurally more similar to the HiPIP isolated from Ectothiorhodospira halophila than to the protein obtained from Chromatium vinosum. In fact, the E. vacuolata molecule is as structurally close to the C. vinosum HiPIP as it is to the E. halophila protein due to the presence of various insertions and deletions that disrupt local folding.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed2000

Molecular structure and cytotoxicity of 3D-transition metal complexes capable to form a stable metal-nitrogen bond.

The cytotoxicity of several Co(II), Ni(II), Cu(II) and Zn(II) complexes with various molecular structures and geometries, has been tested on LoVo and 2008 cells at 1-100 microM concentration for 24 h exposure. On the basis of 24 h results, the exposure time was prolonged to 48 and to 72 hours. The most potent complexes result [Cu(tren)(H2O)]2+ 2Cl-, E, [CoCl3(H2Meppz)], G, and [CoCl3(HMe2ppz)], H, (tren=tris(2-aminoethyl)amine, H2Meppz=1-methylpiperazin-1-ium, HMe2ppz=1,4-dimethylpiperazin-1-ium cations). Nevertheless, these complexes are able to induce cell growth reduction of about 50% at highest doses tested (1-100 microM ) and after 72 h exposure.

Adenocarcinoma↗
PubMed2007

Influence of intramolecular cross-links on the molecular, structural and functional properties of PEGylated haemoglobin.

The influence of intramolecular cross-links on the molecular, structural and functional properties of PEGylated {PEG [poly(ethylene glycol)]-conjugated} haemoglobin has been investigated. The sites and the extent of PEGylation of haemoglobin by reductive alkylation are not influenced by the presence of an alphaalpha-fumaryl cross-link at Lys-99(alpha). The propylated hexaPEGylated cross-linked haemoglobin, (propyl-PEG5K)(6)-alphaalpha-Hb, exhibits a larger molecular radius and lower colloidal osmotic pressure than propylated hexaPEGylated non-cross-linked haemoglobin, (propyl-PEG5K)(6)-Hb. Perturbation of the haem microenvironment and the alpha1beta2 interface by PEGylation of haemoglobin is reduced by intramolecular cross-linking. Sedimentation velocity analysis established that PEGylation destabilizes the tetrameric structure of haemoglobin. (Propyl-PEG5K)(6)-Hb and (propyl-PEG5K)(6)-alphaalpha-Hb sediment as stable dimeric and tetrameric molecules, respectively. The betabeta-succinimidophenyl PEG-2000 cross-link at Cys-93(beta) outside the central cavity also influences the molecular properties of haemoglobin, comparable to that by the alphaalpha-fumaryl cross-link within the central cavity. However, the influence of the two cross-links on the oxygen affinity of PEGylated haemoglobin are very distinct, indicating that the high oxygen affinity of PEGylated haemoglobin is not a direct consequence of the dissociation of the haemoglobin tetramers into dimers. alphaalpha-Fumaryl cross-linking is preferred to modulate both oxygen affinity and molecular properties of PEGylated haemoglobin, and cross-linking outside the central cavity could only modulate molecular properties of PEGylated haemoglobin. It is suggested that PEGylation induces a hydrodynamic drag on haemoglobin and this plays a role in the microcirculatory properties of PEGylated haemoglobin.

Alkylation↗
PubMed1993

The molecular structure of corticotropin-induced secreted protein, a novel member of the thrombospondin family.

CISP (corticotropin-induced secreted protein) is a secreted protein recently purified in our laboratory from the conditioned medium of ACTH-treated bovine adrenocortical cells. Partial amino acid sequencing of CISP revealed homology with thrombospondins (TSPs), a family of adhesive proteins and in particular with TSP2. We report here the characterization of the molecular structure of CISP. Analysis of CISP by polyacrylamide gel electrophoresis in the absence or presence of SDS indicated an apparent molecular mass approximately equal to 600 kDa for the unreduced protein and an apparent molecular mass of 195 kDa after reduction by 2-mercaptoethanol. The sedimentation coefficient of CISP determined by ultracentrifugation on sucrose gradients was shifted from 9.7 S in the absence to 5.7 S in the presence of 2-mercaptoethanol. These data are consistent with a trimeric organization of the CISP molecule in which 195-kDa monomers would be linked together by disulfide bonds. The trimeric structure of CISP could be observed by rotary shadowing/electron microscopy, where CISP appeared to be composed of three equally electron-dense nodules and of a fourth nodule formed by the close association of three smaller fragments. The overall size of the molecule was 60 nm. We also observed that CISP is sulfated and glycosylated. Using glycosylation inhibitors, we could determine that CISP is synthesized as a 175-kDa core protein, is then matured into a 190-kDa high-mannose form and secreted as a 195-kDa mature protein. Inhibition of sulfation by chlorate did not prevent CISP secretion, whereas inhibition of glycosylation by tunicamycin blocked it. Taken together, these data indicate that the TSP2-related CISP molecule presents both structural and functional properties very similar to those of TSP1. CISP differs greatly, however, from TSP1 by the inducibility of its synthesis by cAMP.

Adrenal Cortex↗