Alison Rodger

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.

Symmetry selection rules for reaction mechanisms

Abstract The quantum description of a potential energy surface is shown, in the context of simple transition state theory, to lead naturally to a two-stage symmetry selection procedure for reaction mechanisms which is philosophically consistent with the generalized selection rule approach recently developed for spectroscopic processes. The first stage is the determination of those reaction mechanisms that are strictly allowed by symmetry, and is related to those approaches in which spatial symmetry is used to eliminate certain transition state symmetries. The second stage, which addresses the question of the relative probabilities of the symmetry-allowed mechanisms, is related to orbital symmetry approaches to reaction mechanisms.

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(GCG CGCGGC )2 and d (ATATATATAT) 2 decamers allowed a rationalization of the observed experimental differences for binding to these two helices. Ford (ATATATA AT) 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.

Theoretical studies of the intercalation of 9-hydroxyellipticine in DNA.

Extensive molecular dynamics (MD) simulations have been used to investigate the intercalative binding of 9-hydroxyellipticine to the DNA oligonucleotide d(ATATATATATAT)2. Four independent simulations differing in the initial orientation of the drug at the intercalation site were carried out, and compared both with each other and a control simulation of the free DNA sequence. The structure of the latter was compared with structures obtained from x-ray crystallography and nmr spectroscopy, as well as the theoretically derived alternating B-DNA model [A. Klug et al. (1979), Journal of Molecular Biology, Vol. 131, p. 669]. The alternation of twist angles observed in experimental structures was reproduced in the simulation. All four independent simulations of the drug-DNA intercalation complex converged in placing the pyridine ring of the ellipticine chromophore in the major groove; in one case this involved a 180 degrees rotation of the drug at the intercalation site. At a more detailed level, the drug is seen to be capable of adopting several distinct orientations, each stable over a period of hundreds of pico-seconds. Despite the presence of several polar groups in the drug, however, no direct hydrogen bonding to the DNA occurs; instead, interactions between the methyl groups of the drug and the thymine bases at the intercalation site appear important in determining the orientational preferences of the drug. Comparison of the intercalation complexes with the free DNA sequence shows a degree of unwinding resulting from intercalation, in good agreement with experimental results, but spread over the three central base-pair steps, not confined to the intercalation site itself. Measurements of torsional rigidity indicate only a slight stiffening of the DNA restricted to the immediate site of intercalation. The structures obtained from the MD simulations were used to calculate theoretical CD spectra, with separate simulations giving very different results. This appears to indicate that given an accurate assignment of the main electronic transition dipole moment of the ellipticine chromophore, discrimination of the more realistic binding geometries may be possible. The relative merits of the various drug orientations observed in the simulations are discussed and a perpendicular orientation of the drug at the intercalation site is considered to be the most consistent with experimental data. While the simulations themselves represent a total of over 2 ns, however, the differences apparent between independent runs indicate that longer simulation times will be required before a complete, unequivocal view of DNA intercalation is obtained.

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.

Multiple binding modes with DNA of anthracene-9-carbonyl-N1-spermine probed by LD, CD, normal absorption, and molecular modelling compared with those of spermidine and spermine

DNA groove-binding and intercalative binding modes of anthracene-9-carbonyl-N1-spermine have been probed using linear and circular dichroism, and normal absorption techniques. Despite its lower positive charge, anthracene-9-carbonyl-N1-spermine stabilises DNA more than does spermine and significantly more than spermidine. Data interpretation has been facilitated by molecular modelling.

A ligand-ligand interaction model for the structures of transition metal clusters

Abstract The model previously applied to the rationalization of simple mononuclear complexes of the type MLn has been extended to transition metal cluster carbonyls. Application to the series of carbonyls Mn2(CO)10, Fe2(CO)9, Co2(CO)8, Fe3(CO)12, Ru3(CO)12, and the two isomers of Ir6(CO)16 reveal the importance of ligand-ligand attractive interactions and that crystal packing forces play an important role in deciding the structure adopted and, in some cases, are sufficient to cause the adopted structure to be different from that expected on the basis of intramolecular forces alone.

Polyhedral rearrangements in clusters

Abstract Alternative reaction mechanisms for the rearrangements of cluster compounds containing from five to twelve atoms (or units of atoms) are deduced using purely geometrical arguments and the fact that cluster structures are determined by strong attractive forces between component units. This forms the first stage of a two-stage procedure. The results of the first stage apply to all clusters of a given geometry and the second stage involves quantitative consideration of the electronic states of a given system to determine the relative energetics of the geometrically determined mechanisms.

Geometrical and orientational isomers in clusters

Abstract A new approach to the greater understanding of orientational and geometrical isomers in substituted carbonyl clusters is given with specific application to Fe 3 (CO) 12− n L n .

n–π* Circular dichroism of planar zig-zag carbonyl compounds

A qualitative molecular orbital analysis has been developed to explain both the enhancement of magnitude and the red shift of the circular dichroism spectra of the first n–π* transition of carbonyl compounds which adopt a ‘planar zig-zag’ or ‘W’ conformation.