Role of stacking interactions in the binding sequence preferences of DNA bis-intercalators: insight from thermodynamic integration free energy simulations.
The major structural determinant of the preference to bind to CpG binding sites on DNA exhibited by the natural quinoxaline bis-intercalators echinomycin and triostin A, or the quinoline echinomycin derivative, 2QN, is the 2-amino group of guanine (G). However, relocation of this group by means of introduction into the DNA molecule of the 2-aminoadenine (=2,6-diaminopurine, D) base in place of adenine (A) has been shown to lead to a drastic redistribution of binding sites, together with ultratight binding of 2QN to the sequence DTDT. Also, the demethylated triostin analogs, TANDEM and CysMeTANDEM, which bind with high affinity to TpA steps in natural DNA, bind much less tightly to CpI steps, despite the fact that both adenosine and the hypoxanthine-containing nucleoside, inosine (I), provide the same hydrogen bonding possibilities in the minor groove. To study both the increased binding affinity of 2QN for DTDT relative to GCGC sites and the remarkable loss of binding energy between CysMeTANDEM and ICIC compared with ATAT, a series of thermodynamic integration free energy simulations involving conversions between DNA base pairs have been performed. Our results demonstrate that the electrostatic component of the stacking interactions between the heteroaromatic rings of these compounds and the bases that make up the intercalation sites plays a very important role in the modulation of their binding affinities.
Marco
Esther
E
Departamento de Farmacología, Universidad de Alcalá, E-28871 Alcalá de Henares, Madrid, Spain.
Negri
Ana
A
Luque
F Javier
FJ
Gago
Federico
F
D001483:Base Sequence; D001665:Binding Sites; D003198:Computer Simulation; D018899:CpG Islands; D004247:DNA / Q000737:chemistry; D004448:Echinomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D007364:Intercalating Agents / Q000737:chemistry* / Q000378:metabolism; D011810:Quinoxalines / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
D007364:Intercalating Agents; D011810:Quinoxalines; C075619:(N-MeCys(3)-N-MeCys(7))TANDEM; D004448:Echinomycin; C030309:2QN-echinomycin; D004247:DNA