off the harddrive will give more bandwidth so loading, saving and disk caching will be faster than off a thumb stick.
depending on the amount of ram you have you can setup a memory cache that gimp will set aside for the base image. at default its about 128MB.
you can either select a new image bigger than 2048x2048 @24/32bit colour depth or go into the prefs and set up the cache manually to what ever size you think appropriate.
try not to use more than half your physical ram though as this would force the app to cache to disk which will slow things down dramatically.