I don't think that ergonomics have anything to do with engine displacement. I know that manufacturers usually make their big bikes more comfortable, but I don't see a comfortable 250 impossible at all. Then it won't be a problem to go thousands of miles on such a bike. Iron butt days is another question. 1000 miles one day have to be fast. In my normal pace it's nearly impossible, even without stops if any cities or even villages are involved (ummm... I'd need a bigger tank to do it in one go, and indestructible nerves). No matter the engine displacement in my case, but bigger ones can naturally handle high speeds better.
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