Nucleic Acids Research, 1990, Vol. 18, No. 4 711-717
© 1990
CHEMISTRY |
A theoretical investigation of the base sequence preferences of monointercalating polymethylene carboxamide derivatives 9-amlnoacndine
Université J.Founer LEDSS VI, BP 53F, 38041 Grenoble, France 1Laboratoire de Biochimie Théorique Associé au CNRS, Institut de Biotogie Physico-Chimique, 13 rue Pierre et Mane Curie 75005 Paris, France
Received December 19, 1989. Accepted January 12, 1990.
Theoretical computations are performed of the comparative binding affinities of five polymethylene carboxamide derivatives of 9-aminoacridine to a series of double-stranded hexanucleotides. The purpose of this investigation is to ascertain whether minor groove recognition of a guanine base adjacent to the intercalation site can occur, and be preferentially stabilized, for a given length of the polymethylene side chain, encompassing from n=2 up to n=6 methylene groups. For that purpose, several representative sequences were investigated, in which intercalation of the 9-aminoacridine chromophore occurred at a central d(CpG) or d(TpA) step. Investigated were the self-complementary sequences d(CGCGCG)2 d(GCC GGC)2 d(TATATA)2 and d(ATTAAT)2 as well as the ‘mixed’ sequences d(ACTAAT) .d(ATTAGT) and d(TGTATA). d(TATACA). For n=3 up to n=6, such a recognition was enabled only when the guanine base was located downstream of the Intercalation site, I.e. with steps d(CGG) and d(TAG). it occurred by means of a bidentate interaction involving, on the one hand, H(N2) and N3 of the base, and, on the other hand, the carbonyl oxygen and the cis amino hydrogen of the terminal formamide moiety of the ilgand. Because of the flexibility of the side chain, however, alternative binding modes were also found to occur competitively, involving backbone-only interactions of the side chain.
On the basis of the present computations, upon binding to the sequence d(GCCGGC)2 an optimal value of n=5 could be derived, with the corresponding acridine derivative eliciting both a significant prevalence of the bidentate over backbone only binding mode, and the most favourable energy balance within the investigated series. This privileged value of n=5 is fully consistent with the experimental results of Markovits et al. and Gaugain et al. [1 – 3]. The very flexibility of the side chain, however, hampered any preferential recognition of a triplet sequence with a downstream guanine, such as d(CGG) or d(TAG), to be elicited over sequences such as d(TAA), d(TAT) or d(TAC).