Why would a sub have to go in the middle of the room? What sort of room is it? Where is the seating, if any? Speakers can only go in corners? That actually could help bass-wise by corner loading, but may sound a bit bloaty, too.
I just think one capable pair of speakers can do quite well, and would create a better stereo image, and since you already have the amp, I'd use it, even with a sub (you can make some adjustments depending on which sub, generally at least with the sub's low pass filter, some even provide a high pass filter for speakers). Same goes for the four speakers, if you have them you can try A+B if it suits your purposes, shouldn't be a particular issue for lower volume use.