Computer simulation of antisense DNA containing enantio-deoxynucleotides in the double helix

Computer modeling of DNA double helices containing L-oligodeoxynucleotides and their complementary D-beta-strands in different orientations and conformations was performed using empirical force-field and semiempirical methods. In particular, the parallel and antiparallel orientations of L-alpha and L-beta-configured strands have been extensively simulated. The parallel oriented double helix with L-alpha-2'-deoxynucleotides has been found to be the enantio-deoxynucleotides. The energy difference between this enantio-DNA and native DNA is approximately 6kcal/mol per base pair, favoring the latter. The theoretical results compared well with preliminary experimental data on the hybridization of recently synthesized 11-mer L-oligodeoxynucleotides, L-d-5' (TpCpGpCpTpGpCpTpTpCpT)3' and L-d-5' (TpCpTpTpCpGpTpCpGpCpT)3' containing the complementary D-beta-oligodeoxynucleotides. As predicted by the calculations, experimental results can be interpreted by assuming that hybridization occurs only in the parallel L-alpha-2'-oligodeoxynucleotides.