Sadly, the impression I get from having read slider threads for so many years, both the commentary from their creators and the feedback from users on changes to the sets, it seems like you have to choose between reasonably-realistic gameplay but insufficient challenge, or a good challenge but unrealistic gameplay. This is theoretically because the game is mostly balanced around All-American, which is inherently a tad too easy for most of us, but kicking it up to Heisman just gives the CPU a rather artificial edge by increasing their speed and reaction time (if that's based on outdated info, though, someone feel free to correct me!)
That of course necessitates tweaking the various sliders, but for every change you make, a couple of other things end up getting changed as well, and you'll often end up having to make tweaks to account for *those* changes - the end result being that one small tweak can have a major butterfly effect. Especially given that the game is coded so weirdly that we don't know exactly what all each slider does - some of them have unintuitive effects, and some of them are potentially completely unintended by the devs - I believe in one of the older titles, one of the kicking sliders, accuracy or power, ended up affecting the defense's tackling ability, or something to that effect.
And in 14, I believe the DPI penalty slider correlates with how well DBs cover receivers, and the holding slider increases how well the o-line pass blocks because, well, it makes them hold more - so the penalty sliders end up having a huge effect on the gameplay (again, if that's outdated and someone can correct me, please don't let me misinform folks!)
I use the "50(ish) Threshold Based Slider Set" and I like the gameplay it gives, but the drawback is that it's not quite challenging as would be ideal.
Here's the thread. The OP does a very good job explaining his changes throughout the thread and his posts are often pretty enlightening - the set definitely isn't for everyone but I think it's at least worth skimming through the discussion in the thread. It's pretty informative.