Norleans would be the main trading hub of the region, much like the Hub. It would be a merchant republic like Novgorod, the Free People of Alabama would be based out of the Bayou and would be managed by a council of regional clan leaders (kind of like the Iroquois) and there would be a resurgent Cherokee nation in Northern Georgia/Western North Carolina and would be at war with the Appalachian Republic which would also be fighting the New Confederacy based out of South Carolina which controls Eastern Georgia, Florida, and eastern North Carolina and Virginia.
The Mason-Dixon Line is not to be crossed.
The Mississippi would be about the same as it was, but gigantic steamers would be constantly trafficking the waters, which are now plagued by Radgators, Pikemen (lolpun) and Crab People (not to be confused with Mirelurks or anything like that).
Vaults would be located in Nashville, (former) New Orleans (now Norleans), Miami, Jacksonville, Charlotte, Raleigh, Columbia (SC), Atlanta, Montgomery, and a few others.
Deathclaws, BOS, Super Mutants and other things from the past games wouldn't be there since those aren't native to the region (maybe Enclave). There would be Raddlesnakes (when they shake their rattler it emits radiation), Bigfoots, no feral ghouls just regular ones, Bayou Cannibals, Raider-swamp people, pirates going up and down the Mississippi and the Gulf of Mexico.
Caesar's Legion would be coming in from the West from Texas when the seasonal mile-wide-radioactive tornadoes would die down.
There's also a regional power around Norleans called the Longleaf Order made up of a lot of different city states that works like NATO to fight the Legion.
And you, a simple farm hand chased out of his/her home by unknown attackers, must find the source of these strange beings and save the region from being divided and conquered, or just watching it burn around you.