I do this. I play every play as the safety on the left side of the field (EA needs to make it so that FS and SS flop when necessary). I started doing this in Madden just to add some difficulty to defense, but I actually like it now. It gives me some added freedom as a player.
I run almost strictly man-to-man defense, so I call a lot of cover 1 (or cover 1 Robber). Take the safety (or LB I guess) who is "robbing" the middle of the field and roam with him. You can add some support if it is a run and be there in the middle for when a slot receiver runs a drag or dig route.
Using a safety also gives you more freedom in run committing, I think. I'll often run commit to the side I think the ball is going but keep my safety on the backside in case I'm wrong or the CPU RB cuts back. Usually I'm overpowered by their O-line if I guessed wrong, but it helps to have the backside support nonetheless.