I've been using the 2/50/2 always with the volume down, then on the Axe the output high, poweramp sims on, thump off and cab sims off.
However, amp sims on the Axe and then a real amp behind does blur things a bit. You can compensate by reducing Sag, however the parameter is not linear, so between Sag=0.1 and Sag=0 (which means poweramp=off) there is a huge difference.
So recently I started to run it differently: 2/50/2 cranked, Axe volume to taste, Axe poweramp sims off, cab sims off. I had to put up the bass and mids on my amp patches, but now I'm digging the tone this way more. It's more direct and transparent, you have to take it easy on the VHT's presence, otherwise it can get thin for leads.
Just experiment and see what you like more. If you like poweramp sims on on SOME sounds (e.g. slightly hairy cleans), you can always turn it on in the global setting, and turn Sag=0 on those patches, where you don't want it.