SOLUTION STRUCTURE OF A DNA DODECAMER CONTAINING THE ANTINEOPLASTIC AGENT ARABINOSYLCYTOSINE - COMBINED USE OF NMR, RESTRAINED MOLECULAR-DYNAMICS, AND FULL RELAXATION MATRIX REFINEMENT
Bi. Schweitzer et al., SOLUTION STRUCTURE OF A DNA DODECAMER CONTAINING THE ANTINEOPLASTIC AGENT ARABINOSYLCYTOSINE - COMBINED USE OF NMR, RESTRAINED MOLECULAR-DYNAMICS, AND FULL RELAXATION MATRIX REFINEMENT, Biochemistry, 33(38), 1994, pp. 11460-11475
The effect of araC incorporation into the dodecamer duplex [d(CGCGAATT
)(araC)d(GCG)](2) was examined by comparing its nuclear magnetic reson
ance (NMR)-determined solution structure with that of the control dupl
ex d[(CGCGAATTCGCG)](2). H-1 and P-31 resonances in both duplexes were
assigned using a combination of 2-D H-1 NMR and a 3-D P-31-H-1 hetero
TOCSY-NOESY experiment. Proton-proton distances (determined from NOESY
data) and sugar dihedral angles (from NOESY and COSY data) were used
in restrained molecular dynamics simulations starting from canonical A
- or B-form DNA models. Both the control and araC sets of simulations
converged to B-type structures. These structures were subjected to ful
l relaxation matrix refinement to produce final structures which were
in excellent agreement (R(1/6) < 0.05) With the observed NOE intensiti
es. A detailed comparison of the final control and araC structures rev
ealed a global similarity (overall RMSD similar to 1.3 Angstrom), with
significant differences localized at the araC site and neighboring ba
ses. These included changes in sugar pucker, backbone torsion angles,
base stacking, and other helical parameters. These findings are in gen
eral agreement with the previously published X-ray structure of a deca
mer duplex containing araC. One intriguing feature of the NMR solution
structure not found in the crystal structure is the presence of an in
tramolecular hydrogen bond between the 2' hydroxyl on the araC sugar a
nd the 3' phosphate group.