I think that following the road guides is a pretty fool proof guide to how big city blocks should be in game. The biggest buildings usually fit in it back to back if you follow them. It is pretty boring though. Another down side to following road guides (a grid) is traffic. I have not figured out, yet, the games pathing. It seems agents will take the shortest distance possible even if it is obviously slow.
There can be a traffic jam that, in game time, literally takes 6 hours to clear. More sims will happily pile up behind it and wait, emergency vehicles do not have right of way and will also happily pile up..
Don't know about any of the readers but if traffic was that bad I would go an alternate route. So, short answer to your question: I think it is going to depend on figuring out how the traffic routes and then you will know how big the zoned area should be. Once I know that I will be able to optimize space used for roads with space used for buildings.