Doc, I'm Jim's brother, so I'm the other XXXL rider he spoke of. I have three 2-stroke bikes and two 4-strokes. All are frame-mount, so I have no experience with rack mount or friction drive bikes. Wait, I forgot that I did briefly ride a friend's front-engined friction drive bike several years ago (a BumbleBike), but I really cannot remember much about riding it except that I didn't really care for the thumb lever throttle.
I have built two 2-stroke bikes using 48cc GruBee engines. Both of these are chain-drive and have the standard 50-tooth rear sprocket that came with the kits. I don't know if 50-tooth sprockets now come with them, as I got my kits in 2003 and 2005. They might now come with a different size, as I rarely hear anyone speak of 50-tooth sprockets anymore. With the torque the little 48cc engine has, the 50-tooth sprocket works well with my weight.
However, that is not the case with my 4-stroke build. I have a bike with a 49cc HuaSheng engine with the EZMotorbike Q-Matic drive, and I couldn't even get up to speed with the 50-tooth mounted (the final drive ratio was too tall). I now have a 64-tooth sprocket mounted, and I get up hills nicely as well as having good performance on the flats. In fact, a 260lb friend was riding that bike the other day and I was on my Whizzer, which is a 138c belt-drive bike that has had some performance mods done to it and he walked me going up hill!
The frame-mount 48cc 2-strokes can take me to a little over 30mph on the flats. I can get to almost 40mph with the 4-stroke bike (and over 40 with the Whizzer) on the flats. I don't think that's too bad for a 300lb rider.
In short, with chain final drives I'd suggest staying with larger diameter sprockets in both 2-stroke and 4-stroke applications.
As to the choice of engine, I'm partial to 4-strokes. Not to say that I don't like my 2-strokes, but the 4-stroke doesn't vibrate as much and I think will offer better longevity.