As a seasoned KSP player, I am aware of how important it is during ascent to have center of thrust and center of mass perfectly aligned. If you don't, your rocket will deviate from its course and finally crash.
The Shuttle seems like a pretty obvious asymmetric launch stack. I assume that at liftoff balance was perfect, but how was it maintained when the big tank loses more and more mass? How about the boosters? When they were jettisoned, wouldn't that mean a rather dramatic shift in balance?