TY - JOUR
T1 - Properties of phosphorothioate DNA analogs. An ab initio study of prototype model linkages derived from dimethyl-phosphate anion
AU - Pichierri, Fabio
AU - Sarai, Akinori
N1 - Funding Information:
The authors are grateful to the Japan Society for the Advancement of Technology (JST, Tokyo) and to The Institute of Physical and Chemical Research (RIKEN, Wako) for a generous amount of computer time on their IBM supercomputers. Drs M. Aida (National Cancer Research Center, Tokyo) and H. Torigoe (RIKEN, Tsukuba) are gratefully acknowledged for helpful discussions. We thank Prof. M. Sekine (Tokyo Institute of Technology, Yokohama) for a copy of Ref. [40] . F.P. is indebted to Mr B. Wilcox (University of California, Davis) for a careful reading of the manuscript. F.P. is a recipient of the Fellowship Program sponsored by the Science and Technology Agency (STA) of Japan.
PY - 1999/2/26
Y1 - 1999/2/26
N2 - Ab initio HF and MP2 calculations on prototype model linkages of phosphorothioate DNA backbones illuminate the effects of phosphorothioation on electronic and structural properties of DNA backbone. The replacement of a bridging oxygen atom by sulfur in the phosphodiester linkage is energetically favored over that of replacement of a non-bridging oxygen atom. In phosphorothioate derivatives containing the P(OS)(nb) moiety, the non- bridging oxygen atom always bears a higher negative charge than the non- bridging sulfur. Additional calculations on protonated (neutral) adducts suggest that phosphorothioation of the phosphodiester linkage lowers its proton affinity. Moreover, protonation of the non-bridging oxygen atom at phosphorous is favored over the protonation of the non-bridging sulfur atom for linkages containing the P(OS)(nb) moiety. The ab initio calculated structural parameters are compared to the available crystallographic data of small phosphorothioate molecules and phosphorothioate oligodeoxynucleotides. These results have implications upon the biological activity of phosphorothioate DNA analogs.
AB - Ab initio HF and MP2 calculations on prototype model linkages of phosphorothioate DNA backbones illuminate the effects of phosphorothioation on electronic and structural properties of DNA backbone. The replacement of a bridging oxygen atom by sulfur in the phosphodiester linkage is energetically favored over that of replacement of a non-bridging oxygen atom. In phosphorothioate derivatives containing the P(OS)(nb) moiety, the non- bridging oxygen atom always bears a higher negative charge than the non- bridging sulfur. Additional calculations on protonated (neutral) adducts suggest that phosphorothioation of the phosphodiester linkage lowers its proton affinity. Moreover, protonation of the non-bridging oxygen atom at phosphorous is favored over the protonation of the non-bridging sulfur atom for linkages containing the P(OS)(nb) moiety. The ab initio calculated structural parameters are compared to the available crystallographic data of small phosphorothioate molecules and phosphorothioate oligodeoxynucleotides. These results have implications upon the biological activity of phosphorothioate DNA analogs.
KW - Ab initio MO calculations
KW - Antisense drugs
KW - Phosphorothioate DNA
UR - http://www.scopus.com/inward/record.url?scp=0033605009&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033605009&partnerID=8YFLogxK
U2 - 10.1016/S0166-1280(98)00309-1
DO - 10.1016/S0166-1280(98)00309-1
M3 - Article
AN - SCOPUS:0033605009
SN - 2210-271X
VL - 460
SP - 103
EP - 116
JO - Computational and Theoretical Chemistry
JF - Computational and Theoretical Chemistry
IS - 1-3
ER -