Here's what I use and have pretty decent results.
All Pro
11 minute quarters with 20 seconds left after the run off
0 Threshold
60 Fatigue
35 Injuries
CPU / Player Sliders remain at 50 except the following:
QB Accuracy 41
Interceptions 10
Fumbles 35
Penalty Sliders:
Play around with these depending on how many you want to see. Here are a few that I use, some penalties you will not see anyway such as pass interference no matter what you set it at. Here's just a few of what I use
False start 56
Off sides 60
Clipping 54
Facemask 52
Pass Interference (both) 1
Int. grounding 25
Punt catch interference 25
Popular belief is that the penalty settings affect game play. There's another thread here that goes into detail about that. Also in that thread are the sub in/out numbers that I use.