Abstract
Sixty-four sets of three-dimensional models of RNA-DNA duplex base triplets were constructed based on codons by homology modeling method using software InsightII on Indigo workstation, which should be helpful for the study of RNA-DNA annealing, the basis of nucleic acids interactions and some peculiar motifs for design antisense oligonucleotides. Our research result reveal that the energies (such as E, Ec, Eb, Et and Enr) of DNA/asRNA hybrids are lower than those of RNA/asDNA hybrids while the energies (such as En and End) of DNA/asRNA hybrids are higher than those of RNA/asDNA hybrids for most binary complex and ternary complex, especially E, Ec, Eb and En in evidence. And the total energy of GGG/CCC hybrid is the lowest of all the hybrids, the more G/C base pairs, the lower of energy of the triplet hybrid and (G/C)3<U(G/C)2<A(G/C)2 <U2(G/C)<AU(G/C)<A2(G/C) in turn; the U-including hybrid system stability, the more of number of uracil (U), the lower of energy of the triplet hybrid; the energy of GU-including hybrid is lower than that of CU-including hybrid no matter for binary complex or ternary complex. G/A/U bases often deviate from base pair planes, which can form hydrogen bonds with neighboring base pairs and affects the stabilities of triplets. Moreover, some peculiar oligodeoxynucleotide sequence motifs that could be derived from corresponding triplet hybrids are divided into two groups: four-member motif and five - member motif, where the former comprises eight motifs, namely 5’-TCTT-3’,5’-TGCT-3’,5’-CCTT-3’,5’-CCAT-3’, 5’-CATC-3’, 5’-ATCT-3’, 5’-GCTG-3’ and 5’-GTCT-3’; and the later consists of four motifs, viz 5’-TGCTG-3’, 5’-GTCTT-3’, 5’-CCATC-3’ and 5’-CATCT-3’, which are positively correlated with antisense activities and play an important role in designing antisense drugs.
Highlights
The essential steps in rational drug design are the identification of an appropriate target responsible for a certain disease and the development of a drug with a specific affinity to that target
The energies of 64 K+-RNA/DNA triplet binary complexes, water-K+-triplet ternary complexes and three antisense oligodeoxynucleotide complexes are listed in Table 1 and 2
Our research results reveal that the energies of DNA/asRNA hybrids are lower than those of RNA/asDNA hybrids while the energies of DNA/asRNA hybrids are higher than those of RNA/asDNA hybrids for most binary complex and ternary complex, especially E, Ec, Eb and En in evidence
Summary
The essential steps in rational drug design are the identification of an appropriate target responsible for a certain disease and the development of a drug with a specific affinity to that target. One of the most general approaches of drug targeting is the specific manipulation of gene expression at the DNA or RNA stage of protein synthesis. The first step of protein synthesis can be inhibited by triple helix formation and successively blockade of transcription[3,4]. Dual strand formation in the cytoplasm results in a blockade of protein synthesis in the ribosomes[2,5]. Binding of oligonucleotides to specific sequences may inhibit the interaction of the RNA or DNA with proteins, other nucleic acids or other factors required for essential steps in the intermediary metabolism of the RNA or its utilization by the cell[7]. The study of oligonucleotides, which bind to DNA-DNA duplex to form triplex region, has been reported[8,9]
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