When changing between mods, you do have to be careful, not only with the Save folder, but also with the game folder. Even use of the JSGME "Tasks" utility "Generate snapshot of game files" and then comparing with the similar "Compare game files to snapshot" cannot beat a fresh install of the game, since the compare function can take a good while to run.
Generally speaking, you can copy an original, un-modded SH4 install folder, and paste it to a new folder with a different name, and then apply mods. The use of
MultiSH4 v1.5 allows editing the FileManager.dll of the game, such that you then can have a Save folder for SH4, GFO, TMO, FRS, or whatever 3-character combination you desire to use (no special characters, of course) for each of your game folders. This can keep each of your installs of the game segregated such that they do not overwrite each other.
GFO is basically Stock, with Fixes Only applied, and as such, should not have any issue with Save games, other than what Stock does. Things to remember about the Game and Saves, is that you need a "clean" segment of your hard drive, with plenty of space on it, so that the game isn't having to find little segments of free space to use as it is writing the Save. It is best to have a fast, internal drive if possible. It is also best to keep the number of Save slots down. Do not rely upon the game's automatic Saves, yet don't allow the number of Saves you have get above a screen or two of the listings in the Save dialog.
Most players will save several times during a patrol, just in case something does go wrong, but when they come back in from Patrol, they will clean the folder up, keeping maybe a Save they made as they came back in (in case a conn or other upgrade goes wrong), and then get rid of most of the others, except the game's auto-saves. Then go out on the next patrol and Save again after leaving port, and then anytime encountering anything that might be important. It is best to Save when it it not really busy, also best when you are on the surface at night. This is NOT as important as it was in SH3, where your boat might be diving when you restore the Save, and you cannot recover the dive... that is not cool... SH4 is much better at Saving. But you will still have the occasional hiccup, and it can be very difficult to track down. Your work-around is one of several ways around the issue, and is the easiest to do. But it does tell you that there is an issue somewhere in the system, whether there is something wrong on the hard drive, the game, or whatever. Save again, and then if you have quite a few Saves, get rid of some - but do it from the game's dialog, NOT from the Windows File Manager. Only use File Manager to clear the entire folder contents...