A MODELING 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 descr ibe the in vitro inhibition of transcription of DNA by echinomycin. Th e 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 dissocation rate), with all remaining enzyme being rapidly transferred past that s ite. The solution to the 48 parameters (three per drug site, 16 sites) , which fully described the echinomycin-DNA transcription data set, ca n readily be accomplished without manual intervention within an hour o n a MS-DOS, 486D-based microcomputer, compared to several months for a similar solution by Monte-Carlo simulation (requiring repeated interv ention). The adequacy of the parameters to describe the model was conf irmed by four independent criteria. The approach is applicable to the analysis of any enzyme system where an inhibitor of any type (interact ing in either a reversible or irreversible manner) prevents the proces sive movement of enzyme along the template.