Dinucleotide TpT and its 2'-O-Me analogue possess different backbone conformations and flexibilities but similar stacked geometries.

UV irradiation at 254 nm of 2'-O,5-dimethyluridylyl(3'-5')-2'-O,5-dimethyluridine (1a) and of natural thymidylyl(3'-5')thymidine (1b) generates the same photoproducts (CPD and (6-4)PP; responsible for cell death and skin cancer). The ratios of quantum yields of photoproducts obtained from 1a (determined herein) to that from 1b are in a proportion close to the approximately threefold increase of stacked dinucleotides for 1a compared with those of 1b (from previous circular dichroism results). 1a and 1b however are endowed with different predominant sugar conformations, C3'-endo (1a) and C2'-endo (1b). The present investigation of the stacked conformation of these molecules, by unrestrained state-of-the-art molecular simulation in explicit solvent and salt, resolves this apparent paradox and suggests the following main conclusions. Stacked dinucleotides 1a and 1b adopt the main characteristic features of a single-stranded A and B form, respectively, where the relative positions of the backbone and the bases are very different. Unexpectedly, the geometry of the stacking of two thymine bases, within each dinucleotide, is very similar and is in excellent agreement with photochemical and circular dichroism results. Analyses of molecular dynamics trajectories with conformational adiabatic mapping show that 1a and 1b explore two different regions of conformational space and possess very different flexibilities. Therefore, even though their base stacking is very similar, these molecules possess different geometrical, mechanical, and dynamical properties that may account for the discrepancy observed between increased stacking and increased photoproduct formations. The computed average stacked conformations of 1a and 1b are well-defined and could serve as starting models to investigate photochemical reactions with quantum dynamics simulations.

Biopolymer Chain Elasticity: A novel concept and a least deformation energy principle predicts backbone and overall folding of DNA TTT hairpins in agreement with NMR distances.

A new molecular modelling methodology is presented and shown to apply to all published solution structures of DNA hairpins with TTT in the loop. It is based on the theory of elasticity of thin rods and on the assumption that single-stranded B-DNA behaves as a continuous, unshearable, unstretchable and flexible thin rod. It requires four construction steps: (i) computation of the tri-dimensional trajectory of the elastic line, (ii) global deformation of single-stranded helical DNA onto the elastic line, (iii) optimisation of the nucleoside rotations about the elastic line, (iv) energy minimisation to restore backbone bond lengths and bond angles. This theoretical approach called 'Biopolymer Chain Elasticity' (BCE) is capable of reproducing the tri-dimensional course of the sugar-phosphate chain and, using NMR-derived distances, of reproducing models close to published solution structures. This is shown by computing three different types of distance criteria. The natural description provided by the elastic line and by the new parameter, Omega, which corresponds to the rotation angles of nucleosides about the elastic line, offers a considerable simplification of molecular modelling of hairpin loops. They can be varied independently from each other, since the global shape of the hairpin loop is preserved in all cases.

DNA tri- and tetra-loops and RNA tetra-loops hairpins fold as elastic biopolymer chains in agreement with PDB coordinates.

The biopolymer chain elasticity (BCE) approach and the new molecular modelling methodology presented previously are used to predict the tri- dimensional backbones of DNA and RNA hairpin loops. The structures of eight remarkably stable DNA or RNA hairpin molecules closed by a mispair, recently determined in solution by NMR and deposited in the PDB, are shown to verify the predicted trajectories by an analysis automated for large numbers of PDB conformations. They encompass: one DNA tetraloop, -GTTA-; three DNA triloops, -AAA- or -GCA-; and four RNA tetraloops, -UUCG-. Folding generates no distortions and bond lengths and bond angles of main atoms of the sugar-phosphate backbone are well restored upon energy refinement. Three different methods (superpositions, distance of main chain atoms to the elastic line and RMSd) are used to show a very good agreement between the trajectories of sugar-phosphate backbones and between entire molecules of theoretical models and of PDB conformations. The geometry of end conditions imposed by the stem is sufficient to dictate the different characteristic DNA or RNA folding shapes. The reduced angular space, consisting of the new parameter, angle Omega, together with the chi angle offers a simple, coherent and quantitative description of hairpin loops.