Biomedical subjects

Martin J Packer

Publications and source records attributed to Martin J Packer.

4 recordsLinked to original sources

PubMed2006

Prediction of atomic structure from sequence for double helical DNA oligomers.

DNA can adopt different conformations depending on the base sequence, solvent, electrolyte composition and concentration, pH, temperature, and interaction with proteins. Here we present a model for calculating the three-dimensional atomic structure of double-stranded DNA oligomers. A theoretical energy function is used for calculating the interactions within the base steps and an empirical backbone function is used to restrict the conformational space accessible to the bases and to account for the conformational coupling of neighboring steps in a sequence. Conformational searching on large structures or a large number of structures is possible, because each base step can be described by just two primary degrees of freedom (slide and shift). A genetic algorithm is used to search for low-energy structures in slide-shift space, and this allows very rapid optimization of DNA oligomers. The other base step parameters have been previously optimized for all possible slide-shift sequence combinations, and a heuristic algorithm is used to add the atomic details of the backbone conformation in the final step of the calculation. The structures obtained by this method are very similar to the corresponding X-ray crystal structures observed experimentally. The average RMSD is 2.24 Angstroms for a set of 20 oligomer structures. For 15 of these sequences, the X-ray crystal structure is the global energy minimum. The other 5 are bistable sequences that have B-form global energy minima but crystallize as A-DNA.

Algorithms↗

PubMed2003

Sequence-dependent DNA structure: a database of octamer structural parameters.

We have constructed the potential energy surfaces for all unique tetramers, hexamers and octamers in double helical DNA, as a function of the two principal degrees of freedom, slide and shift at the central step. From these potential energy maps, we have calculated a database of structural and flexibility properties for each of these sequences. These properties include: the values of each of the six step parameters (twist roll, tilt, rise, slide and shift), for each step of the sequence; flexibility measures for both decrease and increase in each property value from the minimum energy conformation for the central step; and the deviation from the path of a hypothetical straight octamer. In an analysis of structural change as a function of sequence length, we observe that almost all DNA tends to B-DNA and becomes less flexible. A more detailed analysis of octamer properties has allowed us to determine the structural preferences of particular sequence elements. GGC and GCC sequences tend to confer bistability, low stability and a predisposition to A-form DNA, whereas AA steps strongly prefer B-DNA and inhibit A-structures. There is no correlation between flexibility and intrinsic curvature, but bent DNA is less stable than straight. The most difficult deformation is undertwisting. The TA step stands out as the most flexible sequence element with respect to decreasing twist and increasing roll. However, as with the structural properties, this behavior is highly context-dependent and some TA steps are very straight.

DNA↗

PubMed2003

Complexation-induced chemical shifts--ab initio parameterization of transferable bond anisotropies.

Complexation-induced changes in proton chemical shifts provide a potent tool for conformational analysis, being highly dependent on intermolecular orientation. An important contribution to these shifts arises from the molecular magnetisability anisotropy, or more specifically from the anisotropy of certain groups, such as aromatic rings and unsaturated bonds. While the influence of aromatic rings has been well characterised via the ring current effect, unsaturated bonds have received much less attention and prediction of complexation shifts is hampered by the lack of accurate anisotropy parameters for these bonds. We have therefore used ab initio calculations at the HF/aug-cc-pVDZ level to obtain bond anisotropies for C-H, N-H, C=O, C=C, C triple bond N, N=N, C triple bond C, and C triple bond N. Fitting the anisotropies to bond magnetic dipoles (the McConnell equation) gives non-transferable values for C-H and N-H bonds. We have therefore expanded in terms of bond magnetic dipoles, quadrupoles, and octopoles for double and triple bonds only, obtaining highly accurate shielding surfaces in all cases. The transferable nature of the anisotropies is confirmed by comparing with shifts obtained in larger molecules containing unsaturated bonds.

Anisotropy↗

PubMed2002

An evaluation of force-field treatments of aromatic interactions.

Experimental measurements of edge-to-face aromatic interactions have been used to test a series of molecular mechanics force fields. The experimental data were determined for a range of differently substituted aromatic rings using chemical double mutant cycles on hydrogen-bonded zipper complexes. These complexes were truncated for the purposes of the molecular mechanics calculations so that problems of conformational searching and the optimisation of large structures could be avoided. Double-mutant cycles were then carried out in silico using these truncated systems. Comparison of the experimental aromatic interaction energies and the X-ray crystal structures of these truncated complexes with the calculated data show that conventional molecular mechanics force fields (MM2, MM3, AMBER and OPLS) do not perform well. However, the XED force field which explicitly represents electron anisotropy as an expansion of point charges around each atom reproduces the trends in interaction energy and the three-dimensional structures exceedingly well. Collapsing the XED charges onto atom centres or the use of semi-empirical atom-centred charges within the XED force field gives poor results. Thus the success of XED is not related to the methods used to assign the atomic charge distribution but can be directly attributed to the use of off-atom centre charges.

Amides↗