Biomedical subjects

I S Haworth

Publications and source records attributed to I S Haworth.

9 recordsLinked to original sources

PubMed1992

A molecular dynamics simulation of a polyamine-induced conformational change of DNA. A possible mechanism for the B to Z transition.

A 75ps molecular dynamics simulation has been performed on a fully solvated complex of spermine with the B DNA decamer (dGdC)5.(dGdC)5. The simulation indicates a possible mechanism by which polyamines might induce the formation of a left-handed helix, the B to Z transition. Spermine was initially located in the major groove, hydrogen bonded to the helix. During the simulation the ligand migrates deeper into the DNA, maintaining strong hydrogen bonding to the central guanine bases and destroying the Watson-Crick base pairing with their respective cytosines. Significant rotation of these and other cytosine bases was observed, in part due to interactions of the helix with the aminopropyl chains of spermine. An intermediate BII conformation might be of importance in this process.

Base Sequence↗

PubMed1991

A molecular mechanics study of spermine complexation to DNA: a new model for spermine-poly(dG-dC) binding.

Molecular mechanics calculations of the binding of spermine to a number of solvated DNA helices have led to the development of a new model for spermine complexation. The structural details of the complexes formed with d(GCGCGCGCGC)2 and d(ATATATATAT)2 decamers allowed a rationalization of the observed experimental differences for binding to these two helices. For d(ATATATATAT)2 it was concluded that spermine remains in a cross-major groove binding site. Conversely, for d(GCGCGCGCGC)2 spermine reorientation via specific ligand-base-pair hydrogen-bond formation allows complexation along the major groove. The solvent plays an important role in differentiating the two binding modes. A mechanism of spermine complexation to natural DNA is postulated from these results. Past experimental data are also considered in the context of the new model.

Base Sequence↗

PubMed1991

COSMIC(90): an improved molecular mechanics treatment of hydrocarbons and conjugated systems.

Four modifications to the COSMIC molecular mechanics force field are described, which greatly increase both its versatility and the accuracy of calculated conformational energies. The Hill non-bonded van der Waals potential function has been replaced by a two-parameter Morse curve and a new H-H potential, similar to that in MM3, incorporated. Hydrocarbon energies in particular are much improved. A simple iterative Hückel pi-electron molecular orbital calculation allows modelling of conjugated systems. Calculated bond lengths and rotational barriers for a series of conjugated hydrocarbons and nitrogen heterocycles are shown to be as accurate as those determined by the MM2 SCF method. Explicit hydrogen-bonding potentials for H-bond acceptor-donor atom pairs have been included to give better hydrogen bond energies and lengths. The van der Waals radii of protonic hydrogens are reduced to 0.5 A and the energy well depth is increased to 1.0 kcal mol-1. Two new general atom types, N+sp2 and O-sp3, have been introduced which allow a wide variety of charged conjugated systems to be studied. A minimum of parameterisation is required, as the new types are easily included in the Hückel scheme which automatically adjusts bond and torsional parameters according to the defined bond-order relationships.

Computer Simulation↗

PubMed1991

Charge calculations in molecular mechanics. Part 8. Partial atomic charges from classical calculations.

The CHARGE2 programme, which involves the classical calculation of both the inductive and resonance contributions to the partial atomic charges in molecules is described, and the charges and electrostatic potentials obtained presented for some illustrative examples. In substituted methanes (CH3X, CF3X, CCl3X) the effects of varying the electronegativity of the substituents and the alpha- and beta-substituent contributions are clearly illustrated for a variety of substituent groups X. The problems involved in the inclusion of silicon into this scheme are detailed, together with the methods of overcoming them. The partial atomic charges (sigma and pi contributions) and electrostatic potentials for some silicon oxygen compounds are presented and discussed. The partial atomic charges from CHARGE2 for all the natural amino acids as their N-acetyl, N'-methylamides are given and compared with those obtained from the AMBER and ECEPP/2 force fields. Considerable differences in these figures are observed, with the AMBER charges consistently much larger than those from the other two methods. The CHARGE2 partial atomic charges and electrostatic potentials for the four common nucleic acids, adenine, cytosine, guanine and thymine, are given and compared with those derived from other calculations. Again there is general similarity but also there are considerable differences, with those from the AMBER force field somewhat larger than the other methods.

Amino Acids↗

PubMed1991

Sequence selective binding to the DNA major groove: tris(1,10-phenanthroline) metal complexes binding to poly(dG-dC) and poly(dA-dT).

Molecular modelling and energy minimisation calculations that incorporate solvent effects have been used to investigate the complexation of delta and lambda-[Ru(1,10-phenanthroline]2+ to DNA. The most stable binding geometry for both enantiomers is one in which a phenanthroline chelate is positioned in the major groove. The chelate is partially inserted between neighbouring base pairs, but is not intercalated. For delta, though not for lambda, a geometry with two chelates in the major groove is only slightly less favourable. Minor groove binding is shown to be no more favourable than external electrostatic binding. The optimised geometries of the DNA/[Ru(1,10-phenanthroline]2+ complexes enable published linear dichroism spectra to be used to determine the percentage of each enantiomer in the two most favourable major groove sites. For delta 57 +/- 15% and for lambda 82 +/- 7% of bound molecules are in the partially inserted site.

Base Sequence↗

PubMed1991

A binding mode of lambda-[tris(1,10-phenanthroline)ruthenium(II)]2+ exhibiting preference for purine-3',5'-pyrimidine sites of DNA.

Molecular mechanics calculations and molecular dynamics simulations have been used to study the binding of the partially inserted major groove complex of Lambda-[Ru(1,10-phenanthroline)3]2+ with DNA. Energy refinements of this complex showed a clear preference for binding at purine-3',5'-pyrimidine sites over pyrimidine-3',5'-purine sites. The basis for this difference is shown to be a slight change in the binding orientation induced by interchanging the purine and pyrimidine bases. This in turn provides for a better secondary interaction with the helix backbone at a point beyond the immediate binding site. It is this secondary interaction that provides the additional energetic stabilisation for complexes formed at purine-3',5'-pyrimidine sites. Molecular dynamics simulations including explicit representation of solvent support these conclusions and provide an insight into the positional stability of the ligand at a particular site. Repuckering of specific deoxyribose rings to the C3'-endo conformation seems to be an important feature of the DNA/ligand complex.

Base Sequence↗

PubMed1991

A prototype bioreductive DNA groove binding ligand.

Molecular mechanics calculations have been used to evaluate the potential bioreductive behaviour of several DNA minor groove binding ligands containing quinone/hydroquinone redox systems. The proposed structures are analogues of the Hoechst 33258 molecule with modifications of the benzimidazole rings. Binding energies of simple analogues indicate the reduced forms bind more strongly to the DNA minor groove. N-methylation of the imidazole ring(s) produces structures which can form extended quinone methides. These also show stronger binding in the reduced form and it is speculated that such structures might provide a basis for the design of groove binding ligands which will act as bioreductive alkylating agents.

Base Sequence↗

PubMed1990

Molecular modelling of poly(aryl ether ketones). I. Aryl..aryl interactions in crystal structures.

Non-bonded potentials for the aryl..aryl interaction have been derived using crystal structure data of a number of small aromatic molecules. The potentials, based on atom-centered interactions, give an accurate reproduction of the benzene crystal geometry and sublimation energy when used in conjunction with coulombic energies evaluated using point atomic charges. An examination of the charge distribution on benzene suggested values of 0.13e (H) and -0.13e (C) to be suitable. The transferability of the potentials has been shown by prediction of crystal geometries and sublimation energies of other hydrocarbon molecules and, with additional interactions for the oxygen atom included, preliminary polymer crystal structure calculations have been carried out. These demonstrate the validity of the derived parameters by successfully predicting crystallographic unit cell dimensions and ring conformations in the poly(phenylene oxide) and poly(aryl ether ketone) crystals.

Computer Simulation↗

PubMed1988

A modification to the COSMIC parameterisation using ab initio constrained potential functions.

The H..H non-bonded potential employed in the current COSMIC force field has been contrasted with H..H potentials used in a number of other force fields. Initial conversion of the variety of functions to a Morse format, achieved using a simple graphical fitting procedure, allowed a direct comparison to be made, showing the COSMIC potential to differ considerably from the other potentials. This difference was reflected in the failure of COSMIC to reproduce ab initio and experimental energies for molecules with significant H..H interactions, with particular reference to the energy curves of benzophenone and diphenyl ether. Considerable improvement in these energies is produced by the use of a Morse function originally based on the H..H potential used in MM3.

Algorithms↗