What set are you playing on?
1) I was testing the CPU run blocking at 50 I think on the black set. My defenders were making plays solo. If I anticipated run I had to stack the box and have the numbers advantage.
2) I agree that with thes sliders and Speed threshold at 0, big plays are prone to happen. It's kind of a give and take. Bumping up the speed threshold (or parity) would help prevent those big plays by CPU. Also, you may have noticed already, but default depth charts has the USER #2 CB against CPU #1 WR. So if you have a weak #2 CB, your prone to big plays. That was my problem early on.
3) This might be a bug. I have not seen fatigue as severe as you stated. Really weird