Are Dinucleoside Monophosphates
Relevant Models for
the Study of DNA Intrastrand Cross-Link Lesions? The Example of G[8–5m]T
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Abstract
Oxidatively generated tandem lesions
such as G[8–5m]T pose
a potent threat to genome integrity. Direct experimental studies of
the kinetics and thermodynamics of a specific lesion within DNA are
very challenging, mostly due to the variety of products that can be
formed in oxidative conditions. Dinucleoside monophosphates (DM) involving
only the reactive nucleobases in water represent appealing alternative
models on which most physical chemistry and structural techniques
can be applied. However, it is not yet clear how relevant these models
are. Here, we present QM/MM MD simulations of the cyclization step
involved in the formation of G[8–5m]T from the guanine–thymine
(GpT) DM in water, with the aim of comparing our results to our previous
investigation of the same reaction in DNA (Garrec, J., Patel, C., Rothlisberger, U., and Dumont, E. (2012) J.
Am. Chem. Soc. 134, 2111−2119). We show that, despite the different levels
of preorganization of the two systems, the corresponding reactions
share many energetic and structural characteristics. The main difference
lies in the angle between the G and T bases, which is slightly higher
in the transition state (TS) and product of the reaction in water
than in the reaction in DNA. This effect is due to the Watson–Crick
H-bonds, which are absent in the {GpT+water} system and restrain the
relative positioning of the reactive nucleobases in DNA. However,
since the lesion is accommodated easily in the DNA macromolecule,
the induced energetic penalty is relatively small. The high similarity
between the two reactions strongly supports the use of GpT in water
as a model of the corresponding reaction in DNA