when i used a guitar hero guitar, here's how i did it.
i was using reason 4 and junxion to set the guitar to control various midi stuff. i set the pick thing to play a C3. when it hit the C3, it would trigger 5 different samples of chords, but they were all muted. so, if i were to just strum it, nothing would happen.
each of the buttons on the neck were set to unmute a different sample. so, if i pressed one down and strummed, it would only play that sample.
it felt just like strumming a real guitar. the whammy bar was set to pitch bend, obv. other buttons let me cycle through different sets of samples (acoustic guitar chords, synth chords, single notes, etc.).
mine had a slider control on the neck that i set to control some delay effects.
it was really fun and i liked my set up a lot more than some people i've seen online who set it so the buttons are what play the notes. i like having use my left and right hands together to make the sounds. it's much more intuitive that way for a guitar player.