Nucleic Acids Research, Vol 27, Issue 10 2189-2195, Copyright © 1999 by Oxford University Press
D Venkateswarlu, KE Lind, V Mohan, M Manoharan and DM Ferguson
The physical properties of a DNA:RNA hybrid sequence
d(CCAACGTTGG)*(CCAACGUUGG) with modifications at the C2'-positions of the
DNA strand by 2'-O-methyl (OMe) and 2'-S-methyl (SMe) groups are studied
using computational techniques. Molecular dynamics simu-lations of
SMe_DNA:RNA, OMe_DNA:RNA and standard DNA:RNA hybrids in explicit water
indicate that the nature of the C2'-substituent has a significant influence
on the macromolecular conformation. While the RNA strand in all duplexes
maintains a strong preference for C3'-endo sugar puckering, the DNA strand
shows considerable variation in this parameter depending on the nature of
the C2'-substituent. In general, the preference for C3'-endo puckering
follows the following trend: OMe_DNA>DNA>SMe_DNA. These results are
further corroborated using ab initio methods. Both gas phase and implicit
solvation calculations show the C2'-OMe group stabilizes the C3'-endo
conformation while the less electronegative SMe group stabilizes the
C2'-endo conformation when compared to the standard nucleoside. The
macromolecular conformation of these nucleic acids also follows an
analogous trend with the degree of A-form character decreasing as
OMe_DNA:RNA>DNA:RNA>SMe_DNA:RNA. A structural analysis of these
complexes is performed and compared with experimental melting point
temper-atures to explain the structural basis to improved binding affinity
across this series. Finally, a possible correlation between RNase H
activity and conformational changes within the minor groove of these
complexes is hypothesized.
ARTICLES
Structural properties of DNA:RNA duplexes containing 2'-O-methyl and 2'- S-methyl substitutions: a molecular dynamics investigation
Department of Medicinal Chemistry and Minnesota Supercomputer Institute, University of Minnesota, Minneapolis, MN 55455, USA.
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