A lot of it comes down to the specific IR/Amp/Guitarsetup one is working it at any given case, but the two most important advanced settings i find myself adjusting almost every time are;
Negative Feedback (Power Amp Section);
I don't know if its only for my ears and my personal preference, but i feel that the default value for most amp models is usually waaay overhyped as far as the negative feedback goes.
This results in the amp sounding extremely muddy and bloated around the 200-400 hz area (as if there's a thick shag rug covering the entire rig).
Specifically for high gain tones, i usually play constant chugs to an instrumental track, while dialing down the negative feedback until i hit that sweet spot where the overall sounds locks in with the rest of the mix.
This usually ends up being anywhere between 1.00-3.00, depending on the situation.
Low Res Freq (Speaker Section):
Again, the default value set on the individual amp, doesn't always match up with [insert cab model], as all cabs have varying resonant peaks from brand to brand.
Some amps have the default value set somewhere around 120-180hz, and in my experience this specific range can become overwhelming when playing palm mutes, resulting in this loud "OOOO"ing boom.
In which case, i scoot down the frequency till the bottom end sounds pleasing and full, usually landing somewhere around 80-90 hz (going any lower than that usually becomes inaudible).
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Other than that, i stick with the basic tone controls, and it usually delivers the goods as promised