Any answer here will depend on how you plan to operate. If you plan to run loops with a few sidings for storage or operations, your loop will be governed by the 48 inch width of a 4x8, whether you set them up as a "U" shape, an "L" shape, or an "I" shape. Thus, you're looking at O42 curve maximums, requiring use of shorter equipment for successful (and less stressful) running.
For anything bigger, you minimally need one more 4x8 sheet and materials to fill in the corners to make an "O" shape layout. With that structure, you should be able to run O72 or larger curves, allowing for the use of much larger equipment. However, now you have to find some way to get into the middle (or be willing to crawl on top of) the layout to fix issues that arise.
Another option would be to create a "U" shape layout with bulbs (maybe 8x8) at each end of the "U" shape. Now, instead of running pure loops, you are running what I call "fake point-to-point" because you can put large reversing loops within each bulb. In this scenario, you can also utilize O72 curves and larger equipment, but your trains could still go round-n-round after passing through the reversing loops created with non-derail switches.
On the other hand, you could run true point-to-point with your basic 3-panel 4x8s and use O72 curves, but this would have to be a short-line railroad designed to do a lot of switching; maybe a transfer yard on one end, a large industrial complex on the other end, and some industries to be switched along the way.
I highly recommend you search for the term "givens and druthers" on the internet. You will find that how you want to operate your trains is just as important as the space you have available (along with many other factors) in determining how to design you layout.
Thank you Chuck... you gave me something to truly think about. I have some bigger equipment that will require O72 curves.... need to figure this out for sure.