How much harder would it be to do the skyrim quest line with DD series and SDplus on?

[Oh shit WTF]

Also, should I play them separately?

[DeWired]

Don't know about SDplus, but I am playing with DD and DCL from the start - and, with right settings and mods, it's totally playable (sometimes, even OP). First of all, I disabled "helpless" conditionals - so, when I meet bandits, they actually start fight first, and only do something else in case of their (unlikely) victory. Second, I have Devious Training installed - which boost my bound combat (after some training period, which I spent doing SLUTS redux deliveries). Third, BWitch - to enable casting even when bound (actually, more powerful, when bound). Fourth, Apocalypse Spell pack - for Ocato' Recital, which autocast spells on combat start - and one of them is Iron/Ebonyflesh to boost armor rating. Alteration perks to boost armor rating when not wearing armor. Also, I have Devious Lore, which helps with getting out of restraints while also leveling you up from that. Right now, I am lv51, I can do a dungeon bound from hands to toes, it seems that I deal and survive more damage when bound compared to heavy armor and sword, last achievement - doing Labyrinthian (with draugr deathlords) with bondage mittens and yoke (on top of everything else). Last unresolved problems that I have with dungeons are doing them in pet suit and opening locks.

[mercplatypus]

It depends on your settings.  Your experience can range anywhere from not noticing too much impact on gameplay, occasional interrupts, play through defining or something that brings everything to a grinding halt.