Txt. Sayle et Jm. Goodfellow, CONFORMATION AND DYNAMICS OF THE MISPAIR O-6-ETHYLGUANINE-THYMINE, Journal of the Chemical Society. Faraday transactions, 92(8), 1996, pp. 1353-1359
Citations number
33
Categorie Soggetti
Chemistry Physical","Physics, Atomic, Molecular & Chemical
Alkylating agents such as N-ethyl-N-nitroso compounds produce G:C to A
:T transition mutations in DNA owing to the ethylation of O-6-guanine.
It is assumed that these mutations occur on replication via mispairin
g of ethylguanine with thymine rather than the normal cytosine. Such a
mispair could be either very stable compared with the normal G:C base
pair or it could be less stable than a normal G:C base pair but cause
little disruption to the DNA, so that it is not easily recognized by
repair enzymes. In this study, the stability and conformation of a dod
ecamer containing O-6-ethylguanine:thymine base pairs has been compare
d with that of a similar duplex containing a normal sequence. rising m
olecular dynamics to study a duplex DNA sequence containing O-6-ethylg
uanine:thymine base pairs, we find a normal Watson-Crick alignment of
the mispairs. However, this conformation is stabilised by only one or
two hydrogen bonds depending on whether the conformation of the ethyl
group is either the cis,trans or the trans,trans orientation with resp
ect to the N(1) of guanine. Analysis of other conformational features
and flexibility has shown that it is difficult to distinguish behaviou
r of the modified sequence with that of the normal sequence. Like the
sequences containing O-6-ethylguanine:cytosine, the modified O-6-ethyl
guanine:thymine sequences are slightly less stable than those containi
ng the normal Watson-Crick G:C sequence. However, both O-6-cis,trans-e
thylguanine:thymine and O-6-trans,trans-ethylguanine:thymine cause ver
y little disruption to the DNA helices in contrast to the behaviour of
O-6-ethylguanine:cytosine and thus the former modifications will be d
ifficult to distinguish from normal sequences by repair enzymes.