A modelling procedure for the analysis of dynamic drug--DNA interactions probed during active transcription of the DNA.
A multicompartment simulation analysis (CONSAM) has been used to describe the in vitro inhibition of transcription of DNA by echinomycin. The model assumes that at all drug blockage sites the fractional amount of blocked RNA polymerase is defined by the relative drug occupancy at that site (and is released at a rate defined by the drug dissociation rate), with all remaining enzyme being rapidly transferred past that site. The solution to the 48 parameters (three per drug site, 16 sites), which fully described the echinomycin-DNA transcription data set, can readily be accomplished without manual intervention within an hour on a MS-DOS, 486D-based microcomputer, compared to several months for a similar solution by Monte-Carlo simulation (requiring repeated intervention). The adequacy of the parameters to describe the model was confirmed by four independent criteria. The approach is applicable to the analysis of any enzyme system where an inhibitor of any type (interacting in either a reversible or irreversible manner) prevents the processive movement of enzyme along the template.
Phillips
D R
DR
Biochemistry Department, La Trobe University, Bundoora, Vic., Australia.
Moate
P J
PJ
Boston
R C
RC
D001483:Base Sequence; D003198:Computer Simulation; D004247:DNA / Q000378:metabolism*; D004448:Echinomycin / Q000494:pharmacology*; D008969:Molecular Sequence Data; D014158:Transcription, Genetic / Q000187:drug effects*
D004448:Echinomycin; D004247:DNA