Full disclaimer: I don't know what I don't know and I'm probably wrong about most of what I do know.
I don't think its the tube pre, honestly. I love a physical tube pre but a lot of that is the physical knobs and switches. In terms of tone, i think the fractal preamps are unbelievably close to the real ones.
I think the real cab is a first order effect on tone but I also find that a tube poweramp and its reaction to a speaker is a big deal. The tube poweramp tends to sound livelier as a result of that interaction. The Axe-FX models the reactivity and there is tuning you can do to try to match your real cabinet but I've yet to get that exactly right, so it has yet to be the equal for me. Lots of people are happy with it as is, though I think part of that is because they don't regularly play a tube amp AND/OR find the considerable advantages of the Axe-FX setup outweighs any shortfall as compared to something with a tube poweramp.
If I disable the poweramp sim or just defeat the reactivity and run into a tube poweramp, its so awesome my head wants to explode.