What happens if you put drives designed for humbuckers through single coils?

Yes this is exactly the issue. Same amp model used in G&R and Metallica presets that cause this ridiculous tweeter squeal.

Single coils are more trebly. What about putting that amp model through a Les Paul with humbuckers? Exact same issue?

If not is the ONLY solution distance?
After reading that there is an issue with this particular amp why not try a different amp model like the AFD100. Then tweak gain, EQ and whatever else would get you to where you want to be without the negative issues. If you’re really wanting to nail the GnR Slash thing then a potted humbucker equipped guitar would be more helpful otherwise this is all a matter of tweaking things to work with what you have. Including distancing yourself from your speakers.

While some have commented on guys like Hendrix and other famous single coil guys playing high gain. If look at old videos of Hendrix playin live with his guitar volume all the way up and Fuzz Face, etc. the second he stops playing everything is squealing like mad. These aren’t SC, but watch the Wootstock footage of The Who and Pete Townshend. When he has the volume and kicks what probably is a Treble Booster or something when he stops playing for a second it’s squeal city. For us old timers playing with lots of gain was always a balance between uncontrolled clipping and the sound we were trying to achieve. This was back before noise gates, fancy wound and wired pups, better designed amps, etc.. It really should still be considered part of equation regardless of high tech modeling or not.

Also, I get the tweeter aspect making things worse, but the same audio physics apply.
 
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