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Biomedical subjects

D J Barlow

Publications and source records attributed to D J Barlow.

18 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↗
PubMedDate not supplied

Continuous and discontinuous protein antigenic determinants.

Protein antigenic determinants have been classified as continuous or discontinuous. The continuous determinants are composed of residues which are local in the polypeptide sequence, while discontinuous determinants consist of residues from different parts of the sequence, brought together by the folding of the protein to its native structure. Searches made for protein determinants using peptide fragments which compete with protein-antibody complex formation, or peptides that can be used to raise antibodies which crossreact with the native protein, are limited to the simulation of continuous determinants. However, recent experiments suggest that most determinants are discontinuous. We now show, by consideration of protein surfaces, that if the recognition zone between a protein and antibody has the same dimensions as those found for the lysozyme-antibody complex, none of the protein's surface will be 'continuous'. We suggest that all determinants are discontinuous to some extent, and that crossreacting peptides mimic only the 'primary' interaction site. In addition, we show that the parts of a protein's surface which are most continuous fall predominantly in the loops and/or protruding regions. This explains why quantities such as hydrophilicity, accessibility, mobility and protrusion can be used to predict which parts of a polypeptide provide the 'best' antigenic peptides.

Antigen-Antibody Reactions↗