While it's highly unrealistic that my characters could run around for days with over 300lbs of stuff, I accept that it is a concession to the looting aspect of the game. I usually strictly abide by my current carry limit, and do not pick up anything that would over-encumber me unless I am going to immediately use it for either repairs or survival needs, however I have occasionally overridden this with the 'tgm' command when there are only a few items left in an interior and another trip would not be worth it.
Of course, it does not help that I just have to pick up everything in sight that's not nailed down, even though a lot of it is not worth much. I end up needing at least 4 trips out of some interiors due to the sheer volume of low-value crap that is lying all over the place; even though I know full well I will not need the money in the long run, I just have to sell it all.
I experimented with a mod in FO3 that increased carry weight well beyond the usual 300 cap, and found that it didn't really help as much as I thought it would. As a result I am not doing that this time around, but I am in the process of adding many of the 'junk' items to either repair lists or the workbench list to turn into scrap of one kind or another, which will increase their usefulness while removing them from the game economy as something I would sell. I'll still be collecting all that crap, but I won't be turning it into ridiculous amounts of cash anymore.