
First, I'd like to talk about offensive line AI. Your center will always shade left in pass-pro, joining the LG and LT to protect your QB's blind side. He will also tend to block left in the run game, though zone-run plays will modify this correctly. This single quirk changes a lot of things about how the game plays, and makes it a mirror image of "traditional" football roles and responsibilities when facing or using a traditional or "over" 4-3 defense.
In general, run to the offense's left.
Most defensive schemes (4-3, 3-4) have their weaker tacklers at either their #2 DT or the #2 MLB. Furthermore, the #2 corner is on the left and most free safeties are not the trained killers that Polamalu, Sanders, etc are at SS. YMMV when running left against Jared Allen, Keith Rivers, Demarcus Ware, Ed Reed, etc.
BTW, the AI does this against you, so be ready for a lot of runs at your RDT and RE. Your FS will need to tackle HBs on a regular basis.
In general, pass-protect to the offense's right.
Pre-snap, count how many rushers there are on either side of the center and note which side has a "free" lineman, and adjust your pass-pro RB accordingly.
When facing a standard 4-3 front, for example, there are two DL to the left of the center and two DL to his right, so (counting the center) you have 3-blocking-2 to the left and 2-on-2 to the right. If the defense blitzes from your right, you'll face a free rusher, so set your first pass-pro back to "Block Right" and even-up your protection.
In general, when you blitz use your strong-side (left) personnel.
You can (and should) exploit the center's tendencies by blitzing the offense's right side more often than the left. Your LE, LOLB and SS will be your primary sack threats due to the numbers mismatch. Even with custom sliders, free rushers are the primary way I get sacks.
In general, think of your offensive and defensive line's responsibilities as "reversed".
Your LT gets the most help in pass-pro by default; your RT faces the most 1-on-1s. Your LG is your most important interior run-blocker, and your least important pass-protector, and the RG (and maybe your C) needs to pass-pro against the Tommie Harris-es of the world.
Likewise, in a standard 4-3 your LE gets the most 1-on-1 matchups in pass rush, and the RE will face a lot of runs and double-teams in pass-protection. Your #1 DT is your "three-technique" tackle, and your #2 is your NT. Consider flip-flopping the members of both lines in your depth chart, or editing the positions, and make (for example) Jared Allen your starting LE.
Major exception: if you face or run a 4-3 "under" defense (RE wide, LE directly opposite RT), all the traditional roles are as you'd expect. RE & RDT get singled up with LT and LG respectively, #1 DT becomes NT.
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