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Biomedical subjects

D J Barlow

Publications and source records attributed to D J Barlow.

At least 19 recordsLinked to original sources
PubMed1992

The structural mimicry of membrane sterols by tamoxifen: evidence from cholesterol coefficients and molecular-modelling for its action as a membrane anti-oxidant and an anti-cancer agent.

The anti-cancer drug tamoxifen is a potent inhibitor of lipid peroxidation induced by Fe(III)-ascorbate in ox-brain phospholipid liposomes. Similar anti-oxidant effects, but with varying potencies, are also shown by 4-hydroxy-tamoxifen, cholesterol, ergosterol and 17-beta-oestradiol. We now describe a computer-graphic fitting technique that demonstrates a structural similarity between the five compounds. In addition, we have quantified the differences (relative to cholesterol) between the anti-oxidant activities of the compounds in terms of a novel expression referred to here as the cholesterol coefficient (Cc) Finally, we discuss how the inhibitory effect of tamoxifen on lipid peroxidation may result from a membrane stabilization that is associated with a decrease in membrane fluidity. This action may be related to the anti-proliferative effect exerted by tamoxifen on cancer and fungal cells.

Antifungal Agents↗
PubMed1991

VESICA: computer graphics modeling of lipid vesicles.

A vesicle simulation and computer analysis program, VESICA, is described which employs spherical projections of triangularly tessellated icosahedra to produce molecular graphics models of the three-dimensional structures of lipid vesicles. The program is used to analyze the molecular architecture of small unilamellar vesicles of dipalmitoyl-phosphatidylcholine and is demonstrated as a worthwhile investigative tool for determining the factors that govern the minimum vesicle size.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1990

RAMBLE: a conformational search program.

A program, RAMBLE, is described which searches the conformational space of looped or cyclic molecules by random assignment of internal coordinates. Conformations produced are screened for energetically unfavorable intramolecular contacts and are subject to user-supplied constraints in terms of both bonded and nonbonded distances, bond angles, and torsion angles. The methodology employed is discussed in relation to alternative search strategies, and a description is given of its successful application in modeling the structures of cyclohexane, reverse-turn tetrapeptides, and a bacterial siderophore complex.

Cluster Analysis↗
PubMed1990

Proposed solution structure of endothelin.

A model is proposed for the 3-dimensional structure of endothelin, a potent vasoconstrictor and pressor peptide from vascular endothelium. The model is derived through protein structure prediction and circular dichroism studies, and is based on the atomic coordinates for the bee-venom peptide apamin. The model derived shows the same turn-helix motif as observed for apamin and mast-cell degranulating peptide. On the basis of this model we suggest possible strategies for endothelin antagonist design, and note that this motif may be common in a number of peptides acting on channel proteins.

Amino Acid Sequence↗
PubMed1989

Conformational analysis of 9-substituted adenines in relation to their microsomal N1-oxidation.

Metabolic N-oxidation of adenine, 9-methyladenine, 9-benzyladenine, 9-benzhydryladenine and 9-trityladenine has been investigated using hepatic microsomes from hamster, guinea-pig, rabbit, mouse, rat, and dog. N1-Oxide formation occurs with 9-benzyladenine and 9-benzhydryladenine using liver preparations of all species examined, although to different extents. The N-oxidase activity was found, amongst rodents, in the order hamster greater than mouse greater than rabbit greater than rat greater than guinea-pig. Microsomal preparations from dog liver contained a small quantity of P-450 and yet produced a relatively large amount of the N-oxides, possibly indicating that other cytochromes in addition to P-450 may be involved in the N-oxidation of these compounds. The most favourable conformations of these 9-substituted analogues have been established using computer graphics modelling and 1H NMR techniques. Results obtained confirmed the importance of the stereochemical properties of these compounds in relation to N1-oxidation. These observations substantiate and extend our previous findings on the electronic, lipophilic, and stereochemical factors affecting the N-oxidation of adenine derivatives.

Adenine↗
PubMed1988

Helix geometry in proteins.

In this report we describe a general survey of all helices found in 57 of the known protein crystal structures, together with a detailed analysis of 48 alpha-helices found in 16 of the structures that are determined to high resolution. The survey of all helices reveals a total of 291 alpha-helices, 71 3(10)-helices and no examples of pi-helices. The conformations of the observed helices are significantly different from the "ideal" linear structures. The mean phi, psi angles for the alpha- and 3(10)-helices found in proteins are, respectively, (-62 degrees, -41 degrees) and (-71 degrees, -18 degrees). A computer program, HBEND, is used to characterize and to quantify the different types of helix distortion. alpha-Helices are classified as regular or irregular, linear, curved or kinked. Of the 48 alpha-helices analysed, only 15% are considered to be linear; 17% are kinked, and 58% are curved. The curvature of helices is caused by differences in the peptide hydrogen bonding on opposite faces of the helix, reflecting carbonyl-solvent/side-chain interactions for the exposed residues, and packing constraints for residues involved in the hydrophobic core. Kinked helices arise either as a result of included proline residues, or because of conflicting requirements for the optimal packing of the helix side-chains. In alpha-helices where there are kinks caused by proline residues, we show that the angle of kink is relatively constant (approximately 26 degrees), and that there is minimal disruption of the helix hydrogen bonding. The proline residues responsible for the kinks are highly conserved, suggesting that these distortions may be structurally/functionally important.

Amino Acid Sequence↗
PubMed1987

The hydration of protein secondary structures.

The hydration of the main-chain carbonyl (CO) groups in proteins have been studied using infra-red spectroscopy, and computer-graphics analysis of high resolution protein crystal structures. The IR measurements indicate that the strength of water binding to the CO groups is lower in beta-sheet proteins compared with alpha-helical ones. Analysis of the protein crystal structures shows that this is due primarily to differences in the geometry of water-CO group interactions in the two types of secondary structure.

Computer Graphics↗
PubMed1986

Location of 'continuous' antigenic determinants in the protruding regions of proteins.

A simple method is described to locate 'antigenic' peptides from the alpha-carbon co-ordinates of a protein, based on protrusion from the protein's globular surface. A good correlation is found between those parts of a protein which protrude and the experimentally determined antigenic peptides in myoglobin, lysozyme and myohemerythrin. A comparison is made between the use of protrusion index, mobility, solvent accessibility and hydrophilicity for predicting the most likely antigenic peptides.

Epitopes↗
PubMed1984

Conformational studies on the pancreatic polypeptide hormone family.

Pancreatic polypeptide has been extracted and sequenced from a wide range of species. The 36-residue polypeptides have some hormonal characteristics, and show a high degree of sequence homology. Two recently isolated polypeptides, from porcine gut and brain, also show a high degree of sequence homology with the pancreatic polypeptides. It was proposed that these polypeptides were members of a related family. The X-ray determined structure of one member of the family, turkey pancreatic polypeptide, is known to high resolution, but there is no structural information for the others. Studies designed to give an insight into the tertiary structure of these related molecules have been carried out, including model building using interactive computer graphics, circular dichroic spectroscopy and secondary structure prediction using a variety of algorithms. The results indicate that a compact globular conformation, similar to that observed in turkey pancreatic polypeptide may be adopted by all molecules and that this may be more highly conserved than the individual amino acid sequences.

Amino Acid Sequence↗
PubMed1983

Ion-pairs in proteins.

A "working definition" for an ion-pair has been derived based upon analysis of the distance distributions for like- and oppositely charged groups in 38 proteins. Ion-pairs defined according to this criterion (less than or equal to 4 A between charged groups) have been analysed in respect of: (1) the frequencies of different pair types; (2) the residue separations and secondary structural locations of the residues involved; (3) the flexibility of the side-chains involved; (4) their conformation; (5) their environment (accessibility to solvent and proximity to active site or ligand binding regions); and (6) their conservation in related proteins. The results obtained indicate that on average one-third of the charged residues in a protein are involved in ion-pairs and 76% of these are concerned with stabilizing the tertiary (rather than the secondary) structure. Only 17% of ion-pairs are buried, and conservation of the interactions is generally low unless the residues involved have more specific functions to perform. In the light of the results obtained, the role of ion pairs in globular proteins is discussed.

Globins↗