There is a very simple answer. If an interface can put out a maximum level of +20 dBu then it means at + 4 dBu it has 16 dB of headroom. Use a VU meter plugin and set it for -16 ref level. So your initial observation is correct. You can work at -16 dB FS as an rms ref level.
Except you don't have to though. You can work at any ref level in reality. e.g. -20. It just means your interface is putting out 0 dBu at that ref. Or at -18. (your output level will be + 2dBu in this case) You do not have to work at the digital ref level that puts out +4dBu.
There will always be plenty of level in order to feed your powered monitors.
Some USB powered interfaces only put out + 4dBu max level so when you are working down at say -18 for example it means they are only putting out -14 dBu. (Not a lot) That is what you get when you try to run an interface off a 5V power supply. Any decent interface will have an internal power supply with higher supply rails e.g. +/- 15 V for example.
There is a basic standard and it is 0 dBu = 0.775V. +4 dBu = 1.23V It used to be into 600 ohms but now the impedance value has gone and the impedance can be and is usually high. dBu can be used to measure voltages. I have been doing it for years!
Be careful making -12 FS your DAW rms reference. You can clip more easily. I work a lot at -14 but only because my digital mixer is calibrated there and then everything matches nice between the DAW and the mixer. -20 is a great ref for the best headroom. The industry has accepted -18 as a common ref as well. Higher ref levels can be used inside your DAW but mainly in the mastering stages. When I master I recalibrate by VU meters so they are always showing 0 dB VU. But what varies is what level is doing that.
Think more about the internal DAW ref level, not so much what the output from your interface happens to be. At least you have chosen a decent interface and it will have plenty of headroom.
K System has introduced 3 other ref levels compared to the basic industry one (-18) They are -12, -14 and -20. K System also requires you monitor your SPL levels in your control room at the same level no matter what ref level you are using. 85 dB SPL comes to mind. Some say its too loud but I think it is perfect.