A Theoretical Investigation on the Sequence Selective Binding of Daunomycin to Double-Stranded Polynucleotides

Abstract

Theoretical computations are performed on the structural and energetical factors involved in the sequence selective binding of daunomycin (DNM) to six representative self-complementary double-stranded hexanucleotides: d(CGTACG)2,d(CGATCG)2,d(CITACI)2, d(TATATA)2, d(CGCGCG)2 and d(TACGTA)2. The conformational angles of the hexanucleotides are fixed in values found in the representative crystal structure of the d(CGTACG)2-DNM complex. The intermolecular DNM-hexanucleotide interaction energies and the conformational energy changes of DNM upon binding are computed and optimized in the framework of the SIBFA procedure, which uses empirical formulas based on ab initio SCF computations. Among the two regularly alternating hexanucleotides, d(TATATA)2 and d(CGCGCG)2, a stronger binding is predicted for the former, in agreement with experimental results obtained with poly(dA-dT).poly(dA-dT) and poly(dG-dC).poly(dG-dC). Altogether, however, among the six investigated sequences, the strongest complexes are computed for the mixed hexanucleotides d(CGATCG)2 and d(CGTACG)2, containing the intercalation site between two CG base pairs and an adjacent TA base pair. This situation may be related to the increased affinity of DNM for GC rich DNA's and to the situation in the crystal structure of the DNM-d(CGTACG)2 complex. Analysis of the intrinsic base sequence preferences expressed by the individual constituents of DNM, namely the daunosamine side chain, the chromophore ring and its two 9-hydroxyl and 9-acetoxy substituents, reveals that the overall sequence preference found is the result of a rather intricate interplay of intrinsic sequence preferences, in particular at the level of daunosamine and the 9-hydroxyl substituent.(ABSTRACT TRUNCATED AT 250 WORDS)

The anthracycline antibiotics: antitumor drugs that alter chromatin structure

“…Chen et al (32) have performed computational analysis to model the interaction of daunomycin with six duplex hexanucleotides of defined sequence. They inferred from their calculations that the most energetically favorable binding sites for these antibiotics were the triplet sequences of 5 0 -TCG and 5 0 -ACG.…”

“…They inferred from their calculations that the most energetically favorable binding sites for these antibiotics were the triplet sequences of 5 0 -TCG and 5 0 -ACG. (25,32) However, Chaires et al (25) have shown that the requirement for A or T at the 5 0 end is not absolute and that three contiguous GC base pairs form an acceptable binding site although possibly with weaker binding affinity.…”

Sequence selective binding of ditrisarubicin B to DNA: comparison with daunomycin

“…The structure is stabilised by several hydrogen bonds. Theoretical calculations [5] suggest that the C9 hydroxyl group forces which would occur between the daunosamine and the 2-amino group of guanine. In order to clarify the importance of these residues for the sequence selective binding we have performed comparative footprinting studies on ditrisarubicin B, which lacks the C13 carbonyl yet possesses an additional charged group on the first sugar attached to C10.…”

Groove selectivity in the interaction of 9‐aminoacridine‐4‐carboxamide antitumor agents with DNA

“…In the second place, intercalators with bulk ligands attached to them, may well have these ligands located in the major as well as in the minor groove. Thus, the 'second generation' anthracyclines, mitoxantrone and anthrapyrazole, while showing a definite specificity for intercalation between GC base pairs, have their side chains located in the major groove [5,61. For these reasons and in view of the potential importance of this new type of drug as an antitumor agent, we have carried out an explicit computation on the stereochemistry of the intercalative are entirely analogous to those used in our studies on the interaction with oligomeric sequences of daunomycin [7], adriamycin [8], mitoxantrone [5] and anthrapyrazole [6] and will thus not be repeated here. Fig.1 recalls the base numbering in the investigated tetramers, the intercalation occurring between bases 2-3' and 3-2'.…”