Is it a DOS program?
If so, I'd suggest running it in DOS but do everything you can to load high the bare minimum of drivers & software.
The goal is to load as much of the minimum necessary drivers into upper memory ie the memory above 1024 Kb, freeing memory from 0 to the first 640 Kb.
You'll need to use Emm386 & Highmem to do it. Don't load anything that isn't needed to run the sim.