Assume everything you DON'T change remains the same.
I.e. stick to F3 if you can, don't say, "I'd make Van Buren."
Assume you're working for Bethesda.
I'm a big fan of F3 and wouldn't change everything but I think I'd change a few things.
This is your sounding board for it.
Here's my prospective changes
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* Introduce Faction Reputation with the BOS, Enclave, Paradise Falls, Rivet City, Tenpenny Towers, etc.
* As much as I like Talon Company, a PMC makes no sense in the Wasteland. I'd instead have Good Reputation PCs hunted by Paradise Falls Slavers.
* Paradise Falls would have a number of bases around the game, having a much higher prevalence than before.
* The Regulators would have actual characterization and you would have the option of doing Bounty Hunting missions for them. There would be "Sheriffs" at most of the settlements who are all implied to be Regulators.
* I'd actually keep Little Lamplight but make it so they're actually all mutants. They're the same kids from 200 years in the past.
* Keep the BOS as is but I'd make the conflict between them and the Outcasts more visceral. Elder Lyons was sent to wipe out the Super Mutants and has been doing so and establish a Capital Wasteland base for the BOS.
The Outcasts are sick of war and just want to go home to Broken Hills, so they're gathering stuff to assemble a vertibird.
* The ending will have the option to side with Colonel Autumn and the Enclave, the BoS/Rivet City alliance (which you have to organize), or Paradise Falls. Each will have separate ending slides.
* All of the Raider gangs would have names and bases where you could wipe out their leadership and get Good Karma.
We'd also find out that there used to be a bunch more settlements but the Raiders all wiped them out with their populace sold to Paradise Falls.
+ Lots more sickly yellow grass and trees rather than just barren rock.
+ An ending slide.
Otherwise, I'd keep everything.