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 (determ...

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Bibliographic Details
Published in:The journal of physical chemistry. B 2007-08, Vol.111 (31), p.9400-9409
Main Authors: Santini, Guillaume P. H, Pakleza, Christophe, Auffinger, Pascal, Moriou, Céline, Favre, Alain, Clivio, Pascale, Cognet, Jean A. H
Format: Article
Language:English
Subjects:
Biochemistry, Molecular Biology
Chromatography, High Pressure Liquid
Computer Simulation
Dinucleoside Phosphates - chemistry
Kinetics
Life Sciences
Magnetic Resonance Spectroscopy
Methylation
Models, Molecular
Molecular Structure
Photochemistry
Photolysis
Pliability
Thymidine - chemistry
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Summary: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.
ISSN:1520-6106
1520-5207
DOI:10.1021/jp0728656