I'd use the game over screen only in the eventual death of the whole party, even if you somehow screw up the main quest. Though I don't know how that would be signified, in Morrowind if you killed a plot critical NPC, a text pops up telling you that you have inadvertently failed your "destiny" and should probably reload if you want. You can continue playing normally though, you just can't complete the main quest anymore. Though there could be a better way. Like the magisters throwing particularly tough enemies at you until you simply can't beat them and lose. Like the final choice in Half Life 1, where the G-man asks Gordon to choose whether to help him or not. If Gordon chooses (i.e. not going into the portal, not choosing it from a drop down menu) not to help him he teleports Gordon to Xen, with no bullets and an army of aliens ready to pounce him.
