Charles A. Laughton

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We present here the parmbsc0 force field, a refinement of the AMBER parm99 force field, where emphasis has been made on the correct representation of the alpha/gamma concerted rotation in nucleic acids (NAs). The modified force field corrects overpopulations of the alpha/gamma = (g+,t) backbone that were seen in long (more than 10 ns) simulations with(More)
A novel cytochrome P450, CYP4x1, was identified in EST databases on the basis of similarity to a conserved region in the C-helix of the CYP4A family. The human and mouse CYP4x1 cDNAs were cloned and found to encode putative cytochrome P450 proteins. Molecular modelling of CYP4x1 predicted an unusual substrate binding channel for the CYP4 family. Expression(More)
A method for predicting the conformations of protein side-chains, starting from main-chain co-ordinates alone, is described. The method involves the comparison of the local environment of each residue whose side-chain conformation is to be predicted with a database of local environments for the same residue type constructed from an analysis of(More)
Aromatase, a cytochrome P450, catalyzes three consecutive hydroxylation reactions converting C19 androgens to aromatic C18 estrogenic steroids. In this study, eight human aromatase mutants (I133Y, I133W, F235L, I395F, I474Y, I474W, I474M, and I474N) were prepared to evaluate the active site and a proposed hydrophobic pocket of the enzyme that exists in an(More)
It is well recognized that base sequence exerts a significant influence on the properties of DNA and plays a significant role in protein-DNA interactions vital for cellular processes. Understanding and predicting base sequence effects requires an extensive structural and dynamic dataset which is currently unavailable from experiment. A consortium of(More)
Telomeric integrity is required to maintain the replicative ability of cancer cells and is a target for the G-quadruplex-stabilising drug, RHPS4. We report a senescent-like growth arrest in MCF-7 breast cancer cells, within 14-17 days, and a reduction in telomere length (5.2 4.7 and 4.3 kb after 17 days treatment at 0.5 and 1μM respectively). These effects(More)
Flavone and isoflavone phytoestrogens are plant chemicals and are known to be competitive inhibitors of cytochrome P450 aromatase with respect to the androgen substrate. Aromatase is the enzyme that converts androgen to estrogen; therefore, these plant chemicals are thought to be capable of modifying the estrogen level in women. In this study, the(More)
We present a simple method for compression and management of very large molecular dynamics trajectories. The approach is based on the projection of the Cartesian snapshots collected along the trajectory into an orthogonal space defined by the eigenvectors obtained by diagonalization of the covariance matrix. The transformation is mathematically exact when(More)
NMR structures are typically deposited in databases such as the PDB in the form of an ensemble of structures. Generally, each of the models in such an ensemble satisfies the experimental data and is equally valid. No unique solution can be calculated because the experimental NMR data is insufficient, in part because it reflects the conformational(More)
Two short routes to novel methylated pentacyclic quinoacridinium salts have been devised. New compounds display telomerase-inhibitory potency (<1 microM) in the TRAP assay. 3,11-Difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (12d, RHPS4, NSC 714187) has a higher selectivity for triplex and quadruplex DNA structures than the(More)