1 - The big difference that I'm aware of is precombination - In order to cut down on resources (I guess, not like I really know) Bethesda implemented this system where tons of insignificant objects in the game get merged into these pre-combined meshes. Any alteration to any object in that mesh - move it, re-size it, anything breaks the mesh for that cell / worldspace and if I remember correctly, for all adjacent cells. This will absolutely tank your FPS in these areas, and can cause the 'sprint bug' where sprinting gets disabled because the game is having trouble loading adjacent cells (as I understand it).
More mods than you think wind up doing this as well - Halk Hogan's 'Fallout 4 Reworked HD' texture mod, for instance. The reason is because objects that are part of precombined meshes don't respond to texture changes, so if you use his mod some piles of tires will look awesome and others won't.
Which actually brings up another point - this game, as I understand it, really doesn't like loading loose files. You can not use the .esp for HD Reworked Revised if you like (in order to not have it break precombination), you just need to use loose files (and be okay with some objects not receiving texture upgrades) but you can then run into another issue, which is textures taking a loooooong time to load in - the result of not having everything packed in .BA2's and loading from an .esp.
Some mods - such as 'scrap everything' type mods usually break all precombined meshes in the game (in order for them to work properly, they need to) and I've heard of some tweaking that can be done to stabilize your framerate, but I don't know what the 'state of the art' is in relation to this. Never had any success trying to use these types of mods so I just avoid them in general.
I use 1 mod that significantly alters the worldspace and that is Beantown Interiors. Though Kris Takahashi's 'Tales from the commonwealth' is probably a more substantial addition.
2 - BiRaitBec's guide is probably the most current, but is pretty simple and focussed on graphics, doesn't really get into anything fiddly. Slim pickings in Fallout 4 mod guides - Gernash has one but it has become quite outdated and he was trying to do some fairly complex stuff, so unless you really know what you're doing it's prettty likely to wind up broken, and I don't think most of his CR patches will be of any use.
3 - Yeah, MO2 ftw.