N-nitroso compounds are known to modify normal DNA bases chemically an
d result in mutations which are either corrected by repair proteins or
lead to misreading of the code and possibly carcinogenesis. In order
to model the conformation of these modified sequences, we have used mo
lecular dynamics simulations which are commonly applied to the study o
f normal oligonucleotide sequences. As part of this study, we have ext
ended the AMBER force field to allow for the modified base O-6-ethylgu
anine (O-6-EtG) in the self-complementary d(CGCGAGCTCGCG) duplex. Our
results show that the AMBER force field produces stable oligonucleoti
de double helices over 2400 ps. The modified sequence with ethylguanin
e: cytosine base pairs leads to local disruption of the base pair beca
use of the chemical modification of the guanine base but all other bas
e pairs retain their normal conformation. The modified base pair has o
nly two hydrogen bonds and adopts the so-called wobble conformation. I
n principle, there are two likely alkyl group conformations which can
exist in the duplex, namely the trans,trans-ethylguanine (t,t-EtG) and
the cis,trans-ethylguanine (c,t-EtG). The t,t-EtG sequence has a very
similar equilibrium structure to the normal sequence whereas the c,t-
EtG helix unwinds resulting in a helix which is one and a half times i
ts original length. This change in conformation, together with other t
hermodynamic and energetic properties, indicates that c,t-EtG is less
stable than t,t-EtG when paired with cytosine. The resulting structura
l changes are therefore factors that could be used in the recognition
process prior to the repair.