OP here, thanks everyone for providing such thoughtful responses!
For all of the presets that I am creating, even if there are differences in amps and effects, there are a lot of similarities between the presets as well that are static. I always use the Noise Gate on the input of Helix so that way I don't have to use a block for it, and use the LA Studio Comp at the end of all of my chains, and before that a Dynamic Ambience Reverb (usually in stereo because I use studio headphones primarily at home, but obviously these can easily be changed to mono depending on the situation). I also place a mono Low/High Shelf EQ and Parametric EQ block directly after the amp and before any post-amp effects.
After reading everything, it seems like the view that most matches my own is using several presets in song modes with different effects and at least a similar section of amps, of course making sure your levels match and learning how to do gapless presets. There are then a few more questions I have:
1. Is there usually any issues with switching between a preset that is very wet (say, 80's rack style or some sort of W/D/W thing) vs more dry presets? I am wondering if this would have any issues as well just because the change would be more drastic than switching between normal effects.
2. How do you determine which cab/IR you use, if you are only using one? Most clean amps have 1x12 or 2x12 cab, with some exceptions, and then most of the higher gain amps have 4x12 cabs. Does this drastically alter the tones? I guess the speakers play more of a part in the tone than the size of the cabs, but I feel like the size would be an important part as well.
3. When determining the amp/amps to use, this definitely seems like a tough issue to reconcile, at least for my cases. It would be heresy for me to not use a Vox if I'm covering Queen, for example

. I think clean tones seem simple enough: you have Fender-style, Vox-style and solid state/JC-120-style cleans. Crunch seems to get a bit trickier. That’s when Marshalls start coming in, and all their similarly voiced amps. Vox has its own style of crunch sound. Dumble has its own crunch/overdriven style of sound. I’d imagine amps like Mesa and Orange have their own style of crunch sounds. High gain again seems to be ruled by Marshall and Mesa-style tones, 5150 stuff (I put this separate from Marshall because the Peavey and modern EVH models have more gain than the old Brown Sound), Bogner, Diezel, ENGL, Soldano and Revv. How do you guys make your choices here if the gain structures can be vastly different?