My personal attitude is that PCs might not ever get put into a situation where they can affect the metaplot, but if they do end up there, they should be able to succeed or fail on their own merits. In other words, don't turn the game into a non-interactive video game cut scene, just because the group stumbles onto a pivotal moment in the larger story. Don't give major NPCs plot armor just because they are major NPCs. PCs may rarely be powerful enough to go head to head with the power players, but they can be the tipping point or deciding factor, when those power players go up against each other.
I think a good way to think of your campaign is that it is an alternate universe that starts out at some point in the "main" game universe, but can diverge wildly from there.