title: Developing a computational model that accurately reproduces the structural features of a dinucleoside monophosphate unit within B-DNA.
abstract: The ability of a dinucleoside monophosphate to mimic the conformation of B-DNA was tested using a combination of different phosphate models (anionic, neutral, counterion), environments (gas, water), and density functionals (B3LYP, MPWB1K, M06-2X) with the 6-31G(d,p) basis set. Three sequences (5'-GX(Py)-3', where X(Py) = T, U or (Br)U) were considered, which vary in the (natural or modified) 3' pyrimidine nucleobase (X(Py)). These bases were selected due to their presence in natural DNA, structural similarity to T and/or applications in radical-initiated anti-tumour therapies. The accuracy of each of the 54 model, method and sequence combinations was judged based on the ability to reproduce key structural features of natural B-DNA, including the stacked base-base orientation and important backbone torsion angles. B3LYP yields distorted or tilted relative base-base orientations, while many computational challenges were encountered for MPWB1K. Despite wide use in computational studies of DNA, the neutral (protonated) phosphate model could not consistently predict a stacked arrangement for all sequences. In contrast, stacked base-base arrangements were obtained for all sequences with M06-2X in conjunction with both the anionic and (sodium) counterion phosphate models. However, comparison of calculated and experimental backbone conformations reveals the charge-neutralized counterion phosphate model best mimics B-DNA. Structures optimized with implicit solvent (water) are comparable to gas-phase structures, which suggests similar results should be obtained in an environment of intermediate polarity. We recommend the use of either gas-phase or water M06-2X optimizations with the counterion phosphate model to study the structure and/or reactivity of natural or modified DNA with a dinucleoside monophosphate.
authors.affiliation: Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive, Lethbridge, Alberta, Canada T1K 3M4.
authors.forename: Cassandra D M
authors.initials: CD
authors.lastname: Churchill
authors.forename: Stacey D
authors.initials: SD
authors.lastname: Wetmore
mesh_terms: D059371:DNA, B-Form / Q000737:chemistry*; D015226:Dinucleoside Phosphates / Q000737:chemistry*; D005740:Gases / Q000737:chemistry; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D012997:Solvents / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D059371:DNA, B-Form; D015226:Dinucleoside Phosphates; D005740:Gases; D012997:Solvents; D014867:Water